scholarly journals Integration of Targeted Gene Expression Profiling and FDG-PET Radiomics Uncovers Radiometabolic Signatures Associated with Outcome in Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3496-3496
Author(s):  
Saveria Mazzara ◽  
Laura L. Travaini ◽  
Francesca Botta ◽  
Chiara Granata ◽  
Giovanna Motta ◽  
...  
Keyword(s):  
Fdg Pet ◽  
Research Funding ◽  
Prognostic Value ◽  
Cancer Metabolism ◽  
Gene Signature ◽  
Advisory Board ◽  
Ffpe Tissue ◽  
Metabolic Signature ◽  
Diagnostic Biopsy ◽  
Large B Cell

Abstract Metabolic rewiring is a hallmark of cancer and a predominant feature of aggressive lymphoproliferative disorders such as diffuse large B-cell lymphomas (DLBCL), which need a reshaped metabolism in order to meet the increased demands related to rapid cell proliferation. Emerging evidence indicates that chemoresistance is closely related to altered metabolism in cancer. However, the relationship between metabolic rewiring and chemoresistance in lymphoma is yet to be elucidated. Radiomic analysis applied to functional imaging with fluoroedoxyglucose positron emission tomography (FDG-PET) provides a unique opportunity to explore DLBCL metabolism. In this study we hypothesized that distinct gene expression (GEP) signatures might be correlated with specific FDG-PET radiomics signatures, which in turn could be associated with resistance to standard chemoimmunotherapy and DLBCL outcome. First, we retrospectively analyzed a discovery cohort of 48 consecutive DLBCL patients (pts) treated at our center with standard first line R-CHOP/R-CHOP-like chemoimmunotherapy from 2010 to 2018, with available formalin-fixed paraffin embedded (FFPE) tissue from the initial diagnostic biopsy and FDG-PET radiomics data extracted from the same target lesion. Median follow-up was 55 months (range 18-110). We profiled this cohort with targeted-GEP (T-GEP) (NanoString platform), using a custom panel to define the cell of origin (COO) and MYC/BCL-2 levels, and a dedicated panel comprising 180 genes encompassing the most relevant cancer metabolism pathways. By applying the maxstat package we found that a 6-gene metabolic signature was strongly associated with outcome and outperformed the COO, the MYC/BCL-2 status and the International Prognostic Index (IPI) score for progression free survival (PFS) and overall survival (OS) in multivariate analysis. The 6-gene metabolic signature included genes regulating oxidative metabolism and fatty acid oxidation (SCL25A1, PDK4, PDPR) which were upregulated, and was inversely associated with genes involved in glycolytic pathways (MAP2K1, HIF1A, GBE1) which were downregulated. Notably 5-year PFS and OS were 100% and 95% in metabolic signature (met-Sig) low pts vs 24% and 45% in met-Sig high pts respectively (p<0.0001 for PFS and OS). There was no significant association between the COO, MYC/BCL-2 levels, standardized uptake value (SUV), and the 6-gene signature. The prognostic value of the 6-gene signature for OS was validated in 2 large publicly available cohorts of 469 (Sha et al. J Clin Oncol 2019) and 233 (Lenz et al. N Eng J Med 2005) pts. Next, we integrated PET radiomics and T-GEP data. Radiomics analysis (LifeX package) was performed by applying regions of interest semi-automatically, using a 25% SUV max threshold for segmentation. Fifty-five radiomic features (RFs) were extracted and 10 RFs significantly correlated either positively or negatively with the T-GEP metabolic signature (Spearman). After stability evaluation, applying a stepwise feature selection procedure, 4 RFs (Histo Curtosis, Histo Energy, Shape Sphericity, NGLDM Contrast) were used to generate a radiomic signature (hereafter called radiometabolic signature) characterized by the most significant correlation with both the metabolic T-GEP signature (r=0.43, p=0.0027) and PFS (p=0.004). These results (obtained analyzing the lesion of the initial diagnostic biopsy), were confirmed using different target lesions (i.e. the most FDG-avid and the largest lesion), and were validated in a second independent cohort of 64 patients (validation cohort) treated at our center in the same period of time (with no FFPE tissue available). A multivariate analysis performed in the whole cohort of 112 pts (discovery + validation) indicated that the radiometabolic signature retained independent prognostic value in relation to the IPI score and metabolic tumor volume. The robustness of the radiometabolic signature was further confirmed by using a second segmentation method (fixed 2.5 SUV max threshold). These data indicate that oxidative metabolic rewiring could be a powerful adverse prognostic predictor, suggesting the possibility of targeting oxidative metabolism to overcome chemorefractoriness in DLBCL. This study provides the proof of principle for the use of FDG-PET radiomics as a tool for non-invasive assessment of cancer metabolism, and for predicting metabolic vulnerabilities in DLBCL. Figure 1 Figure 1. Disclosures Tarella: ADC-THERAPEUTICS: Other: ADVISORY BOARD; Abbvie: Other: ADVISORY BOARD. Pileri: CELGENE: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY-BOARD; NANOSTRING: Other: ADVISORY BOARD. Derenzini: TAKEDA: Research Funding; BEIGENE: Other: ADVISORY BOARD; ASTRA-ZENECA: Consultancy, Other: ADVISORY-BOARD; TG-THERAPEUTICS: Research Funding; ADC-THERAPEUTICS: Research Funding.

scholarly journals Validation of the Nccn-Ipi for Diffuse Large B-Cell Lymphoma in Latin American Patients: A Study from the Latin-American Group of Lymphomas (GELL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5395-5395
Author(s):  
Brady E. Beltrán ◽  
Victoria Otero ◽  
Marialejandra Torres Viera ◽  
Camila Peña ◽  
Myriam Lucía Rodriguez ◽  
...  
Keyword(s):  
High Risk ◽  
Latin American ◽  
Research Funding ◽  
Prognostic Value ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Low Risk ◽  
Score Distribution ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of lymphoma in the world and corresponds to a heterogeneous entity, both from the clinical and molecular point of view, being its prognosis of survival very variable The IPI and the NCCN-IPI are powerful risk-stratification tools in patients with DLBCL. Although the IPI risk score is widely used, it doesn't discriminate very high risk patients. In 2014 the NCCN-IPI was published. It has shown a better discrimination of these patients in Asia, Europe and USA. GELL is a recently formed group of study in lymphomas from Latin America that includes eleven countries. The aim of this study was to validate whether the NCCN-IPI is of prognostic value in Latin-American patients with DLBCL. Methods: We included patients with a diagnosis of DLBCL treated at different institution between 2012-2013. IRB approval was obtained before the collection of the data. Pathological samples were reviewed at each participating institution to confirm the diagnosis. Pertinent clinical data were collected through chart review and are presented using descriptive statistics. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional-hazard regression models were fitted to evaluate hazard ratio (HR) for overall survival (OS). Results: A total of 329 patients with the diagnosis of DLBCL were included in this analysis. The median age at diagnosis was 64 years (range 18-83 years) with a slight female predominance (54%). Clinically, 59% of patients were 60 or older, 34% presented with ECOG >1, 29% with elevated serum LDH, and 70% with extranodal disease; 49% had stage I/II and 51% had stage III/IV. The IPI score distribution was low-risk in 36% of patients, low-intermediate in 25%, high-intermediate in 22% and high-risk 17%. The NCCN-IPI score distribution was low risk in 17%, low-intermediate in 42%, high intermediate in 30% and high risk in 11%. 89% of patients received standard R-CHOP, 2% received R-miniCHOP, and 9% received other regimens. The overall response rate was 83%; 69% had complete response and 14% had partial response. The 5-year overall survival (OS) rate was 65%. DLBCL patients with low, low-intermediate, high-intermediate and high risk NCCN-IPI had 5-year OS rates of 89%, 71%, 55% and 38%, respectively (p<0.001). In a multivariate model adjusting for neutrophil-lymphocyte ratio and lymphocyte-monocyte ratio, NCCN-IPI was an independent prognostic factor. When compared with patients with low-risk NCCN-IPI, patients with low-intermediate (HR 2.0, 95% CI 0.9-4.7; p=0.09), high-intermediate (HR 3.5, 95% CI 1.5-8.0; p=0.003) and high-risk NCCN-IPI (HR 7.2, 95% CI 3.0-17.2; p<0.001) had worse OS. Conclusion: We have validated the prognostic value of the NCCN-IPI in previously untreated Latin American patients with DLBCL. Figure. Figure. Disclosures Chiattone: Janssen: Honoraria, Research Funding. Castillo:Beigene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Janssen: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Consultancy, Research Funding.

scholarly journals Safety and Antitumor Activity Study Evaluating Loncastuximab Tesirine and Rituximab Versus Immunochemotherapy in Diffuse Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Yuliya Linhares ◽  
Mitul D Gandhi ◽  
Michael Chung ◽  
Jennifer Adeleye ◽  
David Ungar ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) who fail immunochemotherapy (IC) and are unsuitable for autologous stem cell transplantation (ASCT) and those who relapse shortly after ASCT have extremely poor prognosis and need additional treatment options. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 2 study (NCT03589469), Lonca demonstrated single-agent antitumor activity with manageable toxicity in patients with relapsed/refractory (R/R) DLBCL. Rituximab is a CD20-targeting monoclonal antibody used in front-line IC for DLBCL and in salvage regimens, such as rituximab/gemcitabine/oxaliplatin (R-GemOx). The addition of rituximab to a CD19-targeting pyrrolobenzodiazepine ADC appears to prolong tumor control in preclinical studies, providing the rationale for evaluating Lonca combined with rituximab (Lonca-R) as a treatment for R/R DLBCL. Study Design and Methods: This is a Phase 3, randomized, open-label, 2-part, 2-arm, multicenter study of Lonca-R versus standard IC in patients with R/R DLBCL (NCT04384484). Part 1 is a nonrandomized safety run-in with Lonca-R. The toxicity of Lonca-R will be compared with previous single-agent Lonca safety data after 20 patients have completed Cycle 1 in Part 1. Provided no significant increase in toxicity is observed, Part 2 will be initiated. Part 2 is a randomized study of Lonca-R versus R-GemOx (Figure 1). Key inclusion and exclusion criteria are reported in Table 1. The primary objective of Part 2 is to evaluate the efficacy of Lonca-R versus R-GemOx, using progression-free survival (PFS) as the primary endpoint. PFS will be defined as the time between randomization and first documentation of recurrence, disease progression or death (central review) and the primary analysis will compare PFS between treatment arms using stratified log-rank testing. Secondary objectives include evaluation of safety, pharmacokinetics, and immunogenicity of the combination, in addition to the impact of treatment on symptoms, patient-reported outcomes and patients' overall health. In Part 1 and in the Lonca-R arm of Part 2, patients will receive intravenous (iv) Lonca at 150 µg/kg on day 1 of each 21-day cycle for 2 cycles, then at 75 µg/kg on day 1 for up to 6 additional cycles. Rituximab 375 mg/m2 iv will be administered subsequent to Lonca infusion on day 1 of each cycle. Patients treated with Lonca-R will also be given dexamethasone 4 mg (oral, twice a day), where not contraindicated, on the day before, the day of, and the day after Lonca-R infusion. In the R-GemOx arm, patients will receive rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatin 100 mg/m2 iv on day 1 of each 14-day cycle up to a total of 8 cycles. Patients will receive premedication and supportive care according to the respective prescribing information for rituximab, gemcitabine, and oxaliplatin. The trial is planned to open in Q3/Q4 2020, and target enrollment is 350 patients. Funding: This study is sponsored by ADC Therapeutics SA; https://clinicaltrials.gov/ct2/show/NCT04384484. Disclosures Linhares: Jazz Pharmaceuticals: Consultancy; ADC Therapeutics, Verastem Oncology, Bristol Myers-Squibb (Juno), AstraZeneca: Research Funding; Miami Cancer Institute, Baptist Health South Florida: Current Employment. Gandhi:TG Therapeutics (Advisory board), GlaxoSmithKline (Advisory board): Membership on an entity's Board of Directors or advisory committees. Adeleye:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ungar:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hamadani:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding. OffLabel Disclosure: Rituximab is licensed for treatment of NHL but is being used in combination with an unlicensed drug (loncastuximab tesirine) in this study

scholarly journals A Prognostic 51-Gene Signature Linked to Abnormal Metaphase Cytogenetics Identifies Myeloma Patients Who Benefit from Fractionated Melphalan Dosing and Added Bortezomib, Thalidomide and Dexamethasone As Conditioning for Autologous Stem Cell Transplant

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3181-3181
Author(s):  
Frits van Rhee ◽  
Alan Mitchell ◽  
Maurizio Zangari ◽  
Jeffery Sawyer ◽  
Sarah Waheed ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Gene Signature ◽  
Advisory Board ◽  
Phase Iii ◽  
University Of Arkansas ◽  
Medical Sciences ◽  
Gene Model ◽  
Advisory Committees

Abstract Introduction: Total Therapy 4 (TT4) comprises a randomized phase III trial enrolling 289 patients with gene expression profiling defined low-risk MM in which patients were allocated to a standard arm (TT4-S) or a light arm (TT4-L) with as principal goal to reduce toxicity yet maintain efficacy in TT4-L. Methods: The TT4-S regimen was similar to TT3b and utilized 2 cycles of VDTPACE induction, tandem transplantation with melphalan 200mg/m2, 2 cycles of dose reduced VDTPACE consolidation and 3 years maintenance with VRD. In TT4-L the number of induction and consolidation cycles was reduced to one each and melphalan was given in a fractionated fashion (50mg/m2/d x 4days) to avoid peak levels of melphalan and reduce mucosal toxicity. Bortezomib and thalidomide were added to the fractionated melphalan conditioning regimen to explore synergistic effects and compensate for potential loss of efficacy. Results: Grade ≥3 toxicities in TT4-S and L occurred with similar frequencies. With a median follow-up of 4.5 years, the OS and PFS were similar in TT4-S and TT4-L at 90 and 87% respectively. The same applied to PFS (TT4-S 84% versus TT4-L 79%). The presence of metaphase defined cytogenetic abnormalities (CA) affected clinical outcomes. In TT4-S, patient with CA had a strong trend toward inferior OS compared to patients with no CA (2 year estimate 83 versus 94%, p=0.08), while the reverse applied to TT4-L (95 versus 81%, p=0.07). Non-significant trends in similar directions were noted for PFS. Complete remission duration tended to be inferior in patients with CA-type MM in TT4-S (2 year estimate, 79 vs. 92%, p=013) with no significant differences in TT4-L. Time to relapse was significantly shorter for CA patients on the TT4-S arm (2 year estimate, 15.4 versus 3.9%), but was not affected by CA in the TT4-L (15.8 vs 7.9%, p=0.79. The observation of CA's favorable OS impact in TT4-L was not anticipated. We next analyzed whether the presence or absence of metaphase CA was linked to specific gene probes which could help to explain better outcomes in TT4-L. Among a training set of 266 untreated patients enrolled in TT3a with available baseline GEP studies, 90 (34%) exhibited CA. Among a test set of 164 patients with baseline GEP accrued to TT3b, 67 (41%) qualified as having CA. Fifty-one probes were different in patients with and without CA (q<0.0001). Seven of the 51 genes had functions in DNA replication, recombination, and repair; five in nucleic acid metabolism, and 4 in RNA post-translational modification and RNA damage and repair. Pathway analysis identified a network of eight interrelated genes that were overexpressed in the CA group, indicating that these MM cells have a higher proliferative activity. We next examined clinical outcomes by the GEP51-CA prediction model in the 2 arms of TT4. In TT4-S, GEP51/no-CA had superior OS and PFS compared to GEP51/CA, which was not observed in TT4-L (Figure 1A, B). Conclusions: A prognostic CA-linked GEP signature can identify patients who benefit from conditioning with fractionated melphalan dosing together bortezomib, thalidomide and dexamethasone which negates the adverse impact of CA. Patients who lacked a CA-type gene signature were best served with single high dose melphalan. These exploratory findings need to be confirmed in a prospective randomized trial. Figure 1. PFS according to 51-gene model predicting CA versus no-CA according to arm (TT4-S, 1A; TT4-L, 1B) Figure 1. PFS according to 51-gene model predicting CA versus no-CA according to arm (TT4-S, 1A; TT4-L, 1B) Disclosures van Rhee: University of Arkansa for Medical Sciences: Employment. Mitchell:Cancer Research and Biostatistics: Employment. Zangari:Millennium: Research Funding; Novartis: Research Funding; University of Arkansas for Medical Sciences: Employment; Onyx: Research Funding. Sawyer:University of Arkansas for Medical Sciences: Employment. Waheed:University of Arkansas for Medical Sciences: Employment. Heuck:Millenium: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Consultancy; Foundation Medicine: Honoraria; University of Arkansas for Medical Sciences: Employment. Thanendrarajan:University of Arkansas for Medical Sciences: Employment. Schinke:University of Arkansas for Medical Sciences: Employment. Jethava:University of Arkansas for Medical Sciences: Employment. Grazziutti:University of Arkansas for Medical Sciences: Employment. Petty:University of Arkansas for Medical Sciences: Employment. Steward:University of Arkansas for Medical Sciences: Employment. Panozzo:University of Arkansas for Medical Sciences: Employment. Bailey:University of Arkansas for Medical Sciences: Employment. Hoering:Cancer Research and Biostatistics: Employment. Crowley:Cancer Research and Biostatistics: Employment. Davies:University of Arkansas for Medical Sciences: Employment; Celgene: Consultancy; Janssen: Consultancy; Onyx: Consultancy; Millenium: Consultancy. Barlogie:University of Arkansas for Medical Sciences: Employment. Morgan:MMRF: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Weismann Institute: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; CancerNet: Honoraria; University of Arkansas for Medical Sciences: Employment; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Discovery of Predictive Gene Signatures for Tumor Sensitivity to MDM2 Inhibition in Development of a Novel MDM2 Inhibitor DS-3032b

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2893-2893 ◽  
Author(s):  
Jo Ishizawa ◽  
Kenji Nakamaru ◽  
Takahiko Seki ◽  
Koichi Tazaki ◽  
Kensuke Kojima ◽  
...  
Keyword(s):  
Cell Lines ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Gene Signature ◽  
Advisory Board ◽  
Wild Type ◽  
Mutation Status ◽  
Gene Signatures ◽  
Gene Set ◽  
Mdm2 Inhibitor

Abstract Development of MDM2 inhibitors enabled successful induction of p53-mediated apoptosis in tumor cells without a risk of DNA damage. Early clinical trials of MDM2 inhibitors demonstrated proof-of-concept (Andreeff et al., Clin Can Res, 2015). However, a clinical challenge is that not all the tumors bearing wild-type TP53 are sensitive to MDM2 inhibition. We here discovered novel gene profiling-based algorithms for predicting tumor sensitivity to MDM2 inhibition, using DS-3032b, a novel potent MDM2 inhibitor, which is currently in early clinical trials. In vitro inhibitory effects of DS-3032b on MDM2-p53 interaction was demonstrated using the homogeneous time resolved fluorescence (HTRF) assay (IC50 5.57 nM). DS-3032b treatment (30-1000 nM) indeed increased p53 protein in a dose-dependent manner, and also the p53 targets MDM2 and p21, in cancer cell lines with wild-type TP53 (SJSA-1, MOLM-13, DOHH-2, and WM-115), showing around 10-fold potent growth inhibition effects compared to Nutlin-3a (Table 1). The xenograft mouse models with SJSA-1 and MOLM-13 cells showed > 90% reduction in tumor growth with oral administrations of 25 and 50 mg/kg/day. For discovering predictive gene signatures, we performed two different approaches. In the first approach, 240 cell lines available as OncoPanel were treated with DS-3032b, another prototypic MDM2 inhibitor DS-5272, and Nutlin-3a, and determined 62 sensitive and 164 resistant lines, based on GI50s. Using gene expression profiling (GEP) publicly available for all the cell lines, we selected 175 top-ranked genes with highest expression in the 62 sensitive cell lines. We thus defined the average of Z-scores of the 175 gene expression as "sensitivity score". To validate the 175-gene signature, we evaluated in vivo anti-tumor activities of DS-3032b in 13 patient-derived tumor xenografts (melanoma, NSCLC, colorectal and pancreatic cancers). The prediction accuracy, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) were 85, 88, 88 and 80% respectively. As another validation set, 41 primary AML samples were treated with DS-3032b to define the top and bottom one-third most sensitive or resistant samples (14 each), and GEP was performed in every sample. TP53 mutations were detected in 8 specimens by next generation sequencing and confirmed by Sanger sequencing. The 175-gene signature was applied to the AML dataset, and the accuracy, sensitivity, PPV and NPV to predict the 14 sensitive or resistant samples were 79, 93, 72 and 90% respectively. Importantly, this signature was more predictive than the TP53 mutation status alone applied (68, 93, 62 and 86%). (Table 2A-B) In contrast to the cell line-based approach, the second approach defined an AML-specific gene signature. Specifically, we used the same dataset of 41 primary AML samples described above as training and validation set, by performing random forest methods with cross validation. Using a routine way in bioinformatics analysis of classifying gene signature, we first selected the 1500 top-ranked genes with highest expression variance among all the specimens. In addition, p53-related 32 genes that potentially have predictive values were also selected based on the previous reports. Classification was performed using the random forest method to identify a predictive algorithm with the 1500-gene set, 32-gene set or combined 1525-gene set (7 genes were overlapped), thus we found that the 1525-gene set had highest performance than each gene set alone. However, applying this method to all the 41 samples showed inferior predictive performance than applied only to the 33 wild-type TP53 samples (the prediction accuracy, sensitivity, PPV and NPV were 68, 72, 67 and 69%, vs. 77, 82, 75 and 80%).(Table 2C) Finally, we combined each of the two algorithms (Table 2B-C) with TP53 mutation status. Specifically, the samples with TP53 mutations were predicted as resistant, then either of gene signatures was applied to the rest of the samples with wild-type TP53. Predictive performance (Table 2D-E) was improved in both signatures compared to the others, especially showing the highest PPVs (80 and 82%, respectively). Taken together, gene signatures discovered in the present study, by combining with TP53 mutation status, provided new highly predictive algorithms for therapy of MDM2 inhibition. Our findings will be tested in ongoing clinical trials of DS-3032b. Disclosures Nakamaru: Daiichi Sankyo Co., Ltd: Employment. Seki:2Daiichi Sankyo Co., Ltd.: Employment. Tazaki:2Daiichi Sankyo Co., Ltd.: Employment. DiNardo:Celgene: Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding. Tse:Daiichi Sankyo, Inc.: Employment.

scholarly journals Prospective Evaluation of 18F-FDG PET/CT As Predictor of Prognosis in Newly Diagnosed Transplant Eligible Multiple Myeloma (MM) Patients: Results from the Imaging Sus-Study of the EMN02/HO95 MM Randomized Phase III Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 992-992
Author(s):  
Elena Zamagni ◽  
Cristina Nanni ◽  
Paola Tacchetti ◽  
Annibale Versari ◽  
Stephane Chauvie ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Fdg Pet ◽  
Research Funding ◽  
Advisory Board ◽  
Response To Therapy ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Pet Ct ◽  
Fdg Pet Ct

Abstract F-18-fluorodeoxyglucose positron emission tomography integrated with computed tomography (FDG-PET/CT) enables to detect with relatively high sensitivity and specificity myeloma bone disease and extramedullary sites of metabolically active clonal plasma cells. FDG-PET/CT has also been used to assess and monitor the metabolic response to therapy and to predict the prognosis. One of the major limitation of PET/CT is the lack of standardized image criteria and of inter-observer reproducibility in interpreting the results. Aim of the present sub-study was to prospectively evaluate FDG-PET/CT at diagnosis, after 4 cycles of induction therapy and prior to maintenance therapy in a sub-group of patients enrolled into EMN02/HO95 MM international phase III trial. In particular, the two primary end-points were firstly to assess the prognostic significance of PET/CT at diagnosis and after therapy and secondly to standardize PET/CT evaluation by centralized imaging and revision and definition of criteria for interpretation. Seven hundred and 18 patients with newly diagnosed transplant-eligible symptomatic MM have been prospectively randomized in Italy from February 2011 through April 2014 to receive 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan and single or double autologous stem cell transplantation (ASCT) as intensification following induction with bortezomib-cyclophosphamide-dexamethasone (VCD). Consolidation therapy with bortezomib-lenalidomide-dexamethasone vs no consolidation was planned after VMP or ASCT(s), followed by lenalidomide maintenance until progression or toxicity. One hundred and three patients were included in the PET/CT imaging sub-study, and followed for a median of 24 months. By study design, PET/CT was performed and analysed in each of the 8 participating centres at baseline, after induction therapy and prior to the start of maintenance (EOT). Each PET scan was a posteriori re-interpreted in a blinded independent central review process, managed by WIDEN®, by a panel of 5 expert nuclear medicine physicians. They described the following characteristics: bone marrow metabolic state (BM), number (Fx) and score (Fs) of focal PET positive lesions, osteolysis (Lx), presence and site of extramedullary disease (EM), and fractures(Fr), according to the IMPeTUs criteria (Nanni et al, EJNM 2015). Moreover, a global score (GS), from 1 to 5, was given to each patient, considering the highest score among BM, Fx, Fs and EM. Concordance among reviewers on different metrics was calculated using Krippendorf's alpha (AK) coefficient Baseline characteristics of the patients were the following: median age 58 years, ISS and R-ISS stage III 15% and 10%, high-risk cytogenetics (t(4;14) ± del(17p) ±del (1p)±1q gain detected by FISH) 42%. At baseline, 78% of the patients had FLs, with a median SUVmax of 6.0. The percentages of PET positive patients for the different characteristics are summarized in table 1. The agreement among reviewer was good for BM (AK=0.49), Fx (AK=0.65), Fs (AK=0.62), Lx (AK=0.62) and EM (AK=0.40). Of all parameters, only Fx ≥ 4 was associated with worse PFS and OS (P = 0.06) Following 4 cycles of VCD, PET/CT remained positive in 59% of the patients, with a median SUVmax of 3.7. Of all parameters, only Fs ≥ 4 was predictive of worse OS (P= 0.05). Prior to maintenance therapy, PET/CT remained positive in 34% of the patients, with a median SUVmax of 3.4. Normal PET/CT findings before maintenance (66%) were associated with a significant improvement in PFS, in particular the following: presence of FLs (P=0.03), Fx ≥ 4 (P=0.001), Fs ≥2 (P=0.03), 3 (P=0.03) and 4 (P=0.006) and SUVmax ≥ 3.4 (p=0.002). GS was also predictive for PFS if ≥ 3 (P=0.033), 4 (P=0.0001) and 5 (P=0.004). The same parameters were also predictive for OS. The prognostic relevance of pre-maintenance PET/CT was retained across the randomization arm (VMP or ASCT), in terms of PFS and OS. In conclusion, PET/CT was confirmed to be a reliable predictor of outcome in newly diagnosed transplant eligible MM patients, whatever the treatment. Normalization of PET/CT before maintenance was associated with a significant improvement for PFS and OS. FDG-PET/CT is by now the preferred imaging technique for evaluating and monitoring response to therapy. Acknowledgments: this study was partially supported by a grant to Elena Zamagni from Fondazione del Monte di Bologna e Ravenna Table 1 Table 1. Disclosures Gay: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees. Larocca:Bristol-Myers Squibb: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Sonneveld:Celgene: Other: Advisory board, Research Funding; Onyx: Other: Advisory board, Research Funding; Millennium: Other: Advisory board, Research Funding; Janssen-Cilag: Other: Advisory board, Research Funding. Cavo:Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria.

The Outcome of Primary Mediastinal Large B-Cell Lymphoma (PMBCL) in the R-CHOP Treatment Era

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 303-303 ◽  
Author(s):  
Kerry J. Savage ◽  
Paul R. Yenson ◽  
Tamara Shenkier ◽  
Richard Klasa ◽  
Diego Villa ◽  
...  
Keyword(s):  
B Cell ◽  
Fdg Pet ◽  
Research Funding ◽  
Who Classification ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Pet Scan ◽  
Chop Chemotherapy ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 303 Background: Primary mediastinal large B-cell lymphoma (PMBCL) was distinguished from DLBCL in the REAL/WHO classification by virtue of distinct clinical and pathologic features. In DLBCL, R-CHOP has demonstrated a clear benefit over CHOP chemotherapy in randomized trials, some of which have included a small subset of PMBCL pts (pts). However, large studies evaluating R-CHOP in PMBCL are lacking. Further, the role of consolidative radiotherapy (RT) to the mediastinum remains unclear particularly with the more frequent use of FDG-PET. At the BCCA, from 2001–2005, R-CHOP with consolidative RT was recommended in all pts with PMBCL. After 2005, FDG-PET scan was used to guide RT usage following 6 cycles of R-CHOP. We evaluated: 1) the outcome of pts with PMBCL in R-CHOP vsCHOP treated pts; 2) prognostic factors in R-CHOP treated pts; 3) the impact of the introduction of PET based approach to guide RT compared to the use routine RT. Methods: Using the BC Cancer Agency Centre for Lymphoid Cancer database, we identified all pts with PMBCL by the REAL/WHO classification treated with R-CHOP in addition to an earlier group treated with CHOP chemotherapy. For R-CHOP treated pts, from 2001–2005, consolidative RT to the mediastinumwas routinely administered following R-CHOP (‘RT’ era). Since 2005, a PET was planned at the end of chemotherapy to guide RT (‘PET’ era). If the PET was negative, pts were observed and if the PET was positive, consolidative RT was given, if feasible. Results: In total, 176 pts were identified: 96 received R-CHOP; 80 received CHOP. Baseline clinical features were similar between the treatment groups. Compared to those treated with CHOP, R-CHOP pts had an improved time to progression (TTP) (5 y 78% vs 65%, p=0.018) and overall survival (OS) (5 y 88% vs 70%, p=0.015). Further, refractory disease (progressive disease (PD) on chemotherapy or relapse < 3 months after treatment completion) was more frequent in CHOP treated pts (16% vs 5%, p=0.016). There was no difference in the risk of central nervous system (CNS) relapse (3.2% vs2.1%, p=0.823). For the R-CHOP treated pts, 46 were treated in the ‘RT era’; 80% received consolidative RT; 50 were treated in the ‘PET era’; 38% received RT. In the RT era, there was a greater proportion of pts with extranodal sites > 1 (p=0.007) and the presence of a pleural/pericardial effusion (p=0.009). In an era to era outcome comparison, there was no difference in the 5 y TTP (RT era 76% vs PET era 83%, p=0.626) or 5 y OS (82% vs 89%, p=0.773). In univariate analysis, the presence of B symptoms was associated with an inferior TTP (5 y 67% vs 90%, p=0.014) and OS (5 y 83% vs 94%, p=0.047). An effusion at diagnosis was associated with an inferior TTP (p=0.017) but not OS (p=0.277). Using recursive partitioning, age > 38 y was identified as the optimal cut-off and was associated with an inferior OS (p=0.003) and there was a trend to a worse TTP (p=0.096). The aaIPI was not predictive of TTP (p=0.357) or OS (p=0.386). In multivariate analysis (including variables with p value<.1 and treatment era), B symptoms (HR 4.3 p=0.011), an effusion (HR 2.97, p=0.025) and age > 38 y (HR 2.98, p=0.025) were associated with an inferior TTP. For OS, age > 38 y (HR 6.7, p=0.003) and B symptoms (HR 4.5, p=0.023) were associated with an inferior outcome. Treatment era (RT vsPET) did not affect TTP or OS in MVA. In total, 59 pts treated with R-CHOP had a PET scan at the end of treatment, 50 in the PET era and 9 pts in the ‘RT era’ by self-pay: 35 (59%) were PET-negative (neg) (2 received RT) and 24(41%) were PET-positive (pos) (23 received RT). With a median follow-up of 5.4 y, there was no difference in the TTP (5 y 78% vs 83%, p=0.735) or OS (5 y 88.5% vs 95%, 0.271) for PET-neg and PET-pos cases, respectively. In total, there were 6 relapses in PET-neg cases: 2 CNS and 4 mediastinal. There were 4 relapses in the PET pos cases (PD in the mediastinum at PET scan n=1; within in RT field n=1; within and outside RT field n=1; outside RT field n=1). Conclusion: We confirm the superior outcome using R-CHOP compared to CHOP chemotherapy in PMBCL, however, rituximab does not appear to impact the rare risk of CNS relapse. The introduction of a PET-guided RT approach in R-CHOP treated PMBCL pts has maintained excellent outcomes in the majority of pts while reducing the use of RT. The presence of B symptoms at diagnosis was associated with an increased risk of relapse and may reflect more aggressive underlying disease biology. Disclosures: Savage: Roche: Research Funding. Klasa:F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Villa:F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Slack:F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Gascoyne:F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Connors:Roche: Research Funding. Sehn:F. Hoffmann-La Roche (Roche Canada): Research Funding.

Clonal-Heterogeneity and Propensity for Bone Metastasis in Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3370-3370
Author(s):  
Yuji Mishima ◽  
Michele Moschetta ◽  
Jiantao Shi ◽  
Francois Mercier ◽  
Salomon Manier ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Gene Signature ◽  
Advisory Board ◽  
Clonal Heterogeneity ◽  
Advisory Committees ◽  
Primary Tumors ◽  
Synonymous Mutations ◽  
Bm Niche

Abstract Rationale Multiple Myeloma (MM) is characterized by the presence of multiple disease foci disseminated throughout the skeleton suggesting continuous circulation and metastasis of myeloma cells from one site of the bone marrow (BM) to another leading disease progression. However the metastatic process in MM has not been well characterized. In addition, the role of specific subclones that have the propensity for metastasis and tumor colonization in the BM niche has not been investigated. In this study, we developed a new BM metastasis xenograft model to examine clonal heterogeneity in tumor colonization of distant bone niches. We identified a set of genes that characterize potential driver genes for metastasis in MM by genomic and transcriptomic profiles of metastatic and primary tumor clones. Methods The model was developed by performing bilateral femur transplantation from donor SCID-bg mice to the dorsum of recipient mice of the same background. To study metastasis, the donor femurs were injected with MM cells (human MM1S, IM-9 and murine 5TGM1) and then implanted in the recipient mice. At the time of hind limb paralysis, the BM cells were flushed from the host or implanted femurs and analyzed by flow-cytometry. To investigate clonal heterogenity, IM-9 cells were transformed with four fluorescent proteins (FPs) simultaneously and sorted into fifteen subpopulations of all combinations of FPs. A mixture composed by equal proportion of all 15 FPs-labeled cells (rainbow mixture) was prepared and then used for in vivo experiment. At the time of sacrifice, clonal distribution of metastasized tumors were analyzed and the predominant clones (winner clones) were flow-sorted for genomic and transcriptomic studies. Library preparation and sequencing were performed according to manufacturer's protocols. Sequencing data was processed by bcbio_nextgen. Briefly for RNA-seq data, raw reads were aligned to reference human genome GRCh37, and gene-level read counts were calculated. Data normalization and differential expression were analyzed with DESeq2. For DNA-seq data, raw reads were aligned to GRCh37. Somatic single nucleotide variants and INDEL were called by MuTect and Indelocator, respectively. Results All myeloma cell lines studied were able to metastasize from the BM of transplanted femurs to the host BM and mice eventually developed paralysis after 6 to 11 weeks. Experiments using rainbow cells consistently showed that only a sub-clone of single color was able to invade and populate the host BM after metastasis, while all 15 color populations were developed in primary tumors. Interestingly, metastatic clones from different mice had similar expression profiles, although these were labeled by different colors. The studies were confirmed in a second MM cell line (MM1S) showing a similar metastasis gene signature (Fig. A). Differential expression analysis identified 238 genes significantly down regulated in both IM-9 and MM1S metastatic tumors compared to matched primary tumors (FDR < 1%). Pathway enrichment analysis indicated that AP-1, ATF2 and NFAT pathways were significantly over-represented (FDR < 5%) (Fig. A). Moreover, this metastatic signature was significantly repressed in relapsed MM patient samples compared to normal controls (FDR < 7%) using GSE6477 dataset (Fig. B). We also compared mutation fraction (MF) distributions in primary and metastatic tumors using DNA-seq data. There was only one peak in each primary tumor (MF around 0.1), while were two peaks for metastatic samples (MF at 0.1 and 0.4), strongly suggests that metastatic clones are derived from a single subclone (Fig. C). Similar results were observed with analysis of only the non-synonymous mutations (Fig. D). Out of all genes with non-synonymous mutations, we found 11 genes that are also functionally related to the metastatic signature using co-expression networks-based prioritization method. Two genes TET1 and PPP2R3A are indicated as examples (Fig. D). Conclusions Here we show a new model of bone metastasis that can be used to examine mechanisms of cell dissemination and colonization of the BM niche. Our studies demonstrate that specific winner subclones have a higher metastatic potential and are likely driver clones for tumor metastasis in MM. On the molecular level, a metastatic gene signature was found to be consistently down regulated in metastatic tumor samples, and 11 genes were identified as potential drivers. Figure 1 Figure 1. Disclosures Munshi: Janssen Research & Development: Membership on an entity's Board of Directors or advisory committees. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Acetylon: Scientific Founder Other; Oncopep: Scientific Founder Other. Scadden:Fate Therapeutics: Consultancy, Equity Ownership. Ghobrial:Sanofi: Research Funding; Noxxon: Research Funding; BMS: Advisory board, Advisory board Other, Research Funding; Onyx: Advisory board Other.

PROGNOSTIC VALUE OF BASELINE FDG PET PARAMETERS IN HIGH RISK DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS

2019 ◽  
Vol 37 ◽  
pp. 411-411
Author(s):  
I. Fiskvik ◽  
C. Stokke ◽  
L.G. Mikalsen ◽  
A. Loimaala ◽  
J. Schildt ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Fdg Pet ◽  
Prognostic Value ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell
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