ALBERT

Description: Background: PET with fluorodeoxyglucose combined with computed tomography is a major tool for the diagnosis, staging and monitoring of treatment response in clinical oncology. 3′-18Fluoro-3′-deoxy-L-thymidine (18F-FLT) is a nucleoside analog that quickly accumulates in proliferating cells, evaluated in clinical studies in various cancers as a PET radiotracer offering non invasive assessment of cell proliferation in vivo. Preliminary results of a pilot study suggested that this technique could be useful to assess bone marrow (BM) activity and extramedullary hematopoiesis in patients with myelofibrosis (MF). We present the final analysis of the FLT-MF-2009 study (EudraCT Number: 2009-016804-21) confirming that FLT PET could be a new technique useful for MF management. Methods: Main inclusion criteria were: a diagnosis of MF according to WHO criteria; BM biopsy available for centralized review; written informed consent. 18F-FLT PET was performed 1 hour after injection of 18F-FLT (provided by AAA), and consisted in a whole-body acquisition. Two nuclear physicians interpreted images in a blinded fashion independently, qualitatively and according to a visual scale, and patients were classified according to 3 distinct patterns. 18F-FLT uptake was quantified using maximum standardized uptake value (SUVmax) in several sites of the skeleton (axial skeleton, proximal and distal territories of upper and lower limbs), in the spleen and the liver. Analysis of factors affecting the intensity of 18F-FLT uptake in these sites (using PET pattern and SUVmax as the endpoints) was performed by using non-parametric tests. Results: 15 patients (mean age: 62 years) were included between Apr 2011 and Jul 2012. 8 patients had primary (PMF), 3 post-polycythemia vera (PV), and 4 post-essential thrombocythemia (ET) MF. 13 patients had a palpable splenomegaly. 10 patients had the JAK2V617F mutation with a median mutant allele burden of 59% (interquartile range: 29-80%), 1 had a MPL515 mutation. Therapies at time of PET included hydroxyurea (n=1), androgens (n=1), interferon (n=4) and ruxolitinib (n=5); 4 patients had no specific therapy for MF. Three patterns of 18F-FLT PET images were observed. Pattern A (n=3) showed a normal BM activity in the central skeleton, a mild expansion to distal extremities and normal splenic uptake. Pattern B (n= 9) displayed a rather normal pattern of BM activity in the central skeleton associated with marked expansion of BM activity to distal extremities and intense uptake of the tracer in the spleen. Pattern C (n=3) showed a marked reduced hematopoietic activity in the central skeleton but a high uptake in spleen, suggesting the existence of myeloid metaplasia. Quantitative analyses of 18F-FLT uptake using SUVmax permitted the search for correlations with clinical and biological characteristics. Grade 3 fibrosis in BM biopsy was significantly associated with low SUVmax values measured in axial skeleton (p=0.019), proximal upper limbs (p=0.016) and proximal lower limbs (p=0.019). Significantly higher SUVmax values in proximal upper (p=0.014) and lower limbs (p=0.021) were associated with the diagnosis of post-PV- vs. post-ET- or PMF. SUVmax values in proximal upper limbs also correlated with the hemoglobin level (Spearman correlation coefficient: 0.53; p=0.038). No significant correlation was found between SUVmax values in any territory and platelet values, JAK2V617F positivity or allele burden, disease duration. Significantly lower SUVmax values were measured in proximal upper limbs of patients treated with ruxolitinib (3.9 ± 2) compared to patients treated with interferon (11.2 ± 5) or untreated patients (7.7 ± 3.1) (p=0.043). Conclusion: The results of this pilot study suggests that 18F-FLT PET could be a new, objective, non invasive technique useful for the evaluation of malignant hematopoiesis in MF, in terms of diagnosis, staging and for monitoring response to therapy. SUVmax values may discriminate post-PV MF from other forms of MF, and may distinguish patients with grade 3 fibrosis. If this latter finding is confirmed in a larger study, 18F-FLT PET could become a convenient substitute to sequential biopsies for the staging of BM fibrosis during the course of the disease. In addition, distinct SUVmax values were found in patients treated with ruxolitinib, suggesting that 18F-FLT PET could also be useful to monitor the efficacy of therapies in MF. Disclosures Off Label Use: 18F-FLT is an investigational isotope not approved for the imaging of myelofibrosis. Patients treated off-label with interferon were included in the study..

Description: Background: Autologous chimeric antigen receptor (CAR) T cell therapy has shown to be effective in relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) but requires in real world and in Europe at least a 4 weeks period of cell processing. During this "bridging period", patients are vulnerable to disease progression and complications. We sought to characterize bridging therapy strategies. Methods: We performed a retrospective review of patients (pts) with R/R DLBCL treated with commercialized CD19 CAR T cells, either Axicabtagene Ciloleucel (Yescarta) or tisagenlecleucel (Kymriah). Bridging therapy (BT) was defined by any therapy given from enrolment to cell infusion. We divided bridging therapy in 2 groups: high intensity BT (HI, including chemotherapy+/-immunotherapy) and low intensity BT (LI, including monoclonal antibodies rituximab, brentuximab, dexamethasone, lenalidomide). We evaluated toxicity (cytokine releasing syndrome (CRS), CAR-related encephalopathy syndrome (CRES), infections) and efficacy (OS, PFS) after infusion according to the intensity of the BT. Results: 46 pts were enrolled for commercialized CAR T cells (Kymriah n=25, Yescarta n=21) including R/R DLBCL (n=35), TFL (n=5) or PMBL (n=6) between June 2018 and April 2019. The median age was 57 (IQR, 42 to 64). Number of pts with aaIPI 〉 2 was 20. The median number of previous lines was 3 (range 3-5), including 15 autologous stem cell transplants and 2 allotransplants. Median time between enrollment and infusion, and between collection and infusion were 59 (35 to 118) and 40 (32 to 90) days, respectively. Overall, 30 (65%) pts received a HI and 16 (35%) a LI or no bridging therapy. Median number of BT cycles was 2 (range, 1-4). 13 patients had various regimen because of uncontrolled disease. Pts receiving HI presented at enrollment with more elevated LDH (60% vs 31%), more involved extranodal sites (n〉 2, 32% vs 0%), higher IPI (〉2, 77% vs 43%, p=.049), and higher total metabolic tumor volume (TMTV) measured on FDG PET/CT (median, 90 vs 10, p=.002). After BT, 44 pts were infused. 2 pts died before infusion because of a pulmonary infection (n=1) and a lymphoma progression (n=1), both in the HI group. At infusion response evaluation showed that 25 (57%) pts progressed during BT, without difference in the HI or the LI groups (61 % vs 50%). Median TMTV in HI and LI was 95 (10 -256) vs 18 (8 - 44), respectively. After CAR T infusion, 14 pts (32%) developed an infectious disease (7 in the LI group, 7 in the HI group, p=0.31). Median duration of neutropenia (PNN 〈 1000) was 8 days, 7 in the LI and 9 in the HI (p= 0.21). In the LI and HI groups, 11 and 19 pts developed a CRS (0 grade 3-4), 1 and 11 pts developed a CRES (1 and 3 grade 3-4), respectively. The HI/LI did not impact the occurrence of CRS (p=1.00) but that of CRES (p=0.03). Pts with abnormal LDH (p=0.02), high number of courses (p=0.03) or PS〉0 (p=0.049) had a higher risk of CRS, whereas patients with high IPI (p=0.03), and high values of CRP (P=0.02) or decreased albumin levels (p=0.008) had a higher risk of CRES. After CAR T cells infusion, with a median follow up of 5.7 months, the median PFS was not reached in the LI group, and was of 3 months in the HI group (p=0.06). The median OS was not reached in the LI group, and was of 12.5 months in the HI group (p=0.09). In multivariate analyses, IPI was predictor of better PFS, whereas low IPI and TMTV were predictors of better OS. No evidence of any effect of intensity of the BT on OS or PFS was observed in these multivariate analyses. Conclusion: The type of bridging therapies was very heterogeneous. Its intensity was closely related to tumor burden at enrolment. There was no significant difference in terms of efficacy between the HI and LI groups, but a higher frequency of CRES in the HI group. Disclosures Paillassa: Janssen: Other: Bibliography board with young hematologists. Di Blasi:Novartis: Honoraria. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 1741 Background: Positron emission tomography (PET) generally employing fluorodeoxyglucose (FDG) combined with high-resolution structural imaging using computed tomography (CT) is regularly used in the diagnosis, staging and monitoring of treatment response in clinical oncology. 3′-18Fluoro-3′-deoxy-L-thymidine (18F-FLT) is a nucleoside analog that quickly accumulates in proliferating cells, more recently evaluated in various cancers including hematologic malignancies like acute leukemias or lymphomas as a PET radiotracer offering non invasive assessment of cell proliferation in vivo. Published results suggest that this technique could be useful to assess bone marrow (BM) activity and extramedullary hematopoiesis (EMH). However, to our knowledge, only 3 patients (pts) with myelofibrosis (MF) have been explored with 18F-FLT PET/CT (FLT PET). This pilot study aimed to establish proof-of-concept that FLT PET could be a new non invasive technique useful for MF management, in terms of diagnosis, staging and for monitoring response to therapy. Methods: Pts were evaluated using 2 different techniques. First, conventional BM scintigraphy (BMS) was performed: on day 1, pts were injected with 99mTechnetium-nanocolloids and a planar image of the reticuloendothelial system was performed 30 min after injection; pts were then injected with 111Indium-Cl3 and planar imaging of the erythroid BM was performed after 48h. Secondly, FLT PET was performed 1 hour after injection of 18F-FLT (provided by AAA), and consisted in a whole-body acquisition. Images were interpreted in a blinded fashion independently by two nuclear physicians, qualitatively and according to a visual scale for both examinations. In addition, 18F-FLT uptake was quantified using standardized uptake value (SUV) in several sites of the skeleton, spleen and liver. Results: 15 pts (9 men, 6 women, mean age: 62 years) were included between Apr 2011 and Jul 2012 (14 evaluable at time of abstract submission). 7 pts (47%) had primary (PMF), 4 post-polycythemia vera (PV), and 4 post-essential thrombocythemia (ET) MF, respectively (WHO criteria). All the pts had a BM biopsy with quantification of fibrosis. 11 pts (73%) had a JAK2V617F mutation, 1 a MPL515 mutation, and 3 had neither of these mutations. Therapies included hydroxyurea (n=1), androgens (n=1), interferon (n=4) and ruxolitinib (n=5); 4 pts had no specific therapy for MF. Three distinct patterns of FLT PET images were observed. 3 pts showed a marked reduced hematopoietic activity in the central compartment of the skeleton but a high uptake in spleen, suggesting the existence of myeloid metaplasia (Fig 1A). 8 pts had a rather normal pattern of BM activity in the central skeleton associated with marked expansion of BM activity to distal extremities and intense uptake of the tracer in the spleen (Fig 1B). 3 pts showed a relatively normal pattern of BM activity in the central skeleton, a mild expansion to distal extremities with no splenic abnormality (Fig 1C). FLT interpretation in myeloid malignancies is not standardized and we used comparisons with BMS to establish interpretation guidelines. Qualitative FLT PET results were equivalent to the 111In-Cl3 imaging in most cases, but in 2 pts FLT uptake was normal when BMS showed reduced 111In-Cl3 uptake. Compared to BMS, PET will also provide much more information including: (i) quantitative analyses of 18F-FLT uptake using SUV (preliminary results show that SUV ranges are [1.8 – 18.4] and [2.3 – 19.8] in BM and spleen, respectively); (ii) precise evaluation of malignant myelopoiesis in the different anatomical sites using coupled CT images. These analyses, and correlation with clinical and biological characteristics, BM histopathology and type of therapy received are ongoing. Conclusion: FLT PET is a new, convenient non invasive technique for evaluation of malignant hematopoiesis in MF, including BM activity and EMH. Distinct patterns of FLT uptake may help in the diagnosis and staging of MF. In addition, ongoing correlation studies with histological BM fibrosis could provide evidence for a role of this non invasive technique in the assessment of the evolution of fibrosis over time without the need for sequential biopsies. A subsequent clinical trial will determine in a larger cohort of MF pts the usefulness of PET for evaluation of tumor response to therapy and prediction of early response using sequential evaluation of FLT uptake in BM and spleen. Disclosures: Off Label Use: 3′-18Fluoro-3′-deoxy-L-thymidine (18F-FLT) is a nucleoside analog tested as a PET radiotracer in patients with myelofibrosis.

Description: Introduction : High total metabolic tumor volume (TMTV) measured on 18F-FDG PET/CT before R-CHOP has been shown to be significantly associated with worse progression-free survival (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL; Cottereau et al. Clin Cancer Res. 2016;22:3801-9) . The REMARC study (NCT01122472) is an international, multicenter, double-blind, randomized phase III trial that assessed lenalidomide (LEN) maintenance therapy versus placebo (PBO) in 650 patients responding to R-CHOP. With a median follow-up of ~40 months, independent review demonstrated that 2 years of LEN maintenance therapy significantly improved progression-free survival (PFS); median was not reached in the LEN arm vs 58.9 months in the PBO arm (HR=0.71 [95% CI, 0.54-0.93]; p=0.0135; Thieblemont et al. J Clin Oncol. 2017;35:2473-81). Methods: For these analyses, patients enrolled in the REMARC trial who had baseline PET/CT before R-CHOP (not mandatory per study protocol) with available fused images and end of treatment PET/CT were included. Total metabolic tumor volume (TMTV, defined as the sum of the regions of the local tumors with FDG uptake) was measured on baseline PET/CT with the 41% SUVmax thresholding method using the free semiautomatic software Beth Israel Fiji20 (http://petctviewer.org). The optimal TMTV cut-off to PFS (per FDA censoring rule) and overall survival (OS) was determined by Receiver Operating Curve (ROC) curves and X-tile analyses. Survival was estimated using Kaplan Meier (KM) curves. Multivariable analysis were performed with descending Cox model including TMTV, IPIaa, treatment arm and PET/CT response evaluated by Deauville criteria. Analyses were performed on the evaluable population and separate arms Results: 228 of 650 REMARC patients had TMTV data available for analysis, including n=108 in the PBO arm and n=120 in the LEN arm. Clinical characteristics were similar to the overall population. The median baseline TMTV was 295 cm3 (Q1-Q3, 99-702). After a median follow-up of 51.6 mo, 4y-PFS was 73% and 4y-OS was 85%. The optimal TMTV cut-off determined by ROC was 300 cm3 for PFS and OS. Patients with TMTV 〉300 vs ≤300 cm3 presented with worse ECOG performance status (ECOG ≥2: 19% vs 9%, p=0.034), higher Ann Arbor stage (stage III-IV: 95% vs 86%, p=0.042), more extra-nodal sites (〉1: 65% vs 38%, p300 vs ≤300 cm3 on PFS (HR=2.4; 95% CI, 1.1-5.22) and OS (HR=5.0; 95% CI, 1.4-17.) was maintained in the PBO arm (Figure 1A). In contrast, when the analysis was focused on patients in LEN arm, TMTV 〉300 vs ≤300 cm3 lost its prognostic impact on PFS and OS. In the LEN arm, 4-year PFS and OS did not differ significantly between patients with high and low TMTV (Figure 1B). Conclusion: TMTV measured on baseline PET/CT is a strong prognosticator of outcome in DLBCL, even in patients in response after R-CHOP. High TMTV at baseline was significantly associated with worse PFS and OS in patients receiving PBO following a response to R-CHOP in the REMARC study. Interestingly, LEN maintenance reduces the negative impact of high baseline TMTV on survival in patients with DLBCL Disclosures Casasnovas: takeda: Consultancy; merck: Consultancy; MSD: Consultancy; Roche: Consultancy; Gilead Sciences: Research Funding; Roche: Honoraria; Takeda: Honoraria; Merck: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Honoraria; MSD: Honoraria; Roche: Research Funding; Gilead Sciences: Consultancy; Janssen: Consultancy. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees. Feugier:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ribrag:Infinity: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Amgen: Research Funding; Roche: Honoraria, Other: travel; MSD: Honoraria; BMS: Consultancy, Honoraria, Other: travel; epizyme: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; argenX: Research Funding; pharmamar: Other: travel; Incyte Corporation: Consultancy. Macro:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress. Morschhauser:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Janssen: Other: Scientific Lectures; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Trotman:Janssen: Other: Unremunerated member of Ad Board, Research Funding; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Takeda: Other: Unremunerated member of Ad Board; Celgene: Other: Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding; Beigene: Research Funding. Godmer:CELGENE: Other: Invitation to congress. Salles:Servier: Honoraria; Novartis: Consultancy, Honoraria; Morphosys: Honoraria; Servier: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Acerta: Honoraria; Merck: Honoraria; Janssen: Honoraria, Other: Advisory Board; Pfizer: Honoraria; Epizyme: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria; Amgen: Honoraria; Abbvie: Honoraria. Coiffier:CELGENE: Consultancy, Membership on an entity's Board of Directors or advisory committees; MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees; CELLTRION: Membership on an entity's Board of Directors or advisory committees; MORPHOSYS: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees. Meignan:F. Hoffman-La Roche Ltd: Honoraria.

Description: Background. L-asparaginase (L-ASPA) based-chemotherapy (chemo) is one of the most efficient treatment for patients with extra-nodal NK/T nasal type lymphoma, in front- line or at relapse. This treatment is combined either with radiation therapy (RT) if localized or with high dose therapy plus autologous stem cell transplantation (HDT/ASCT) if disseminated. However it may be associated with toxicities that may impair efficacy and survival. Aim. The aim of this study was to report the real-life experience of L-asparaginase use in patients with NK/T nasal type lymphoma treated with L-ASPA based-chemotherapy and to identify risk factors associated with 1/ main adverse events and 2/ survivals. Patients and methods. Between July 2003 and June 2016, 28 patients were treated in our center for NK/T nasal type lymphoma. Four of them were excluded because they did not receive L-ASPA- based chemotherapy. Among the 24 pts included, 21 received the L-ASPA based-chemo as front-line therapy, and 3 pts as second line, either in association with gemzar and dexamethasone (n=14), or with methotrexate and dexamethasone (n=6), or with etoposide and dexamethasone (n=1). RT was delivered in 18 pts; HDT/ASCT in 3 pts; and both in 1 pt. Median number of injections of L-ASPA was 12 per patient (range 3-32). Grade 3-4 of toxicities (tox) were retrospectively assessed according to CTCAE V4.03, with a particular attention to 4 categories: hematological, hemostasis, liver and pancreatic dysfunctions. Progression-free (PFS) and overall survivals (OS) were analyzed from time of first L-ASPA injection, based on Kaplan Meier estimates. Results. Median age at diagnosis was 51 years (interquartile range, IQR : 40.7-61, ranging from 24-78). Sex ratio M/F was 0.71. PS was 〉 2 in 3 patients. Median body mass index (BMI) was 24 kg/m 2 (IQR: 23-25.7, ranging from 17-33). Stage was localized in nasal site in 20 patients, and disseminated (III-IV) in 4 patients, with bone marrow involvement in 2 pts, muscle in 1 pt, skin in 1 pt, and extensive nasal in 1 pt. LDH level was high in 10 (41.7%) patients. At diagnosis, EBV serum DNA was positive in 15/20 (75%) patients. All patients were negative for HBV, HIV, HCV. Abnormal baseline levels of ASAT/ ALAT (〉 2N) were present in 2 patients, amylase/lipase (〉1.5N) in 2 pts, bilirubine (2N) in 4 pts. Baseline anemia (〈 10g/L) and thrombopenia (〈 100 G/L) were present in 6 and 2 patients, respectively. Hemostastic parameters were normal in all patients. During the treatment, 10 (42%) patients developed gr3-4 hepatic toxicities, and 3 (13%) pts pancreatic toxicities, 6 (25%) pts hematologic toxicities, 3 (13%) pts hemostatic toxicities. These toxicities induced a reduction of treatment in 6 (25%) patients. Hematological toxicities were associated to baseline hemoglobin and platelets levels and to poor PS (p= 0.008; p= 0.014 ; p= 0.095, respectively). Hemostatic toxicities were associated to the stage of the disease, but not significantly (p= 0.076). No factor was associated for hepatic or pancreatic toxicities. Age and BMI were not significantly associated to any toxicity. A complete remission was achieved at the end of treatment in 12 patients (50%). At 2 years, progression- free survival and overall survival were 39% (95%CI, 20.3-76%) and 51.5% (95%CI, 30-89%), respectively. Presence of toxicities impacted the progression free survival and overall survival, though not significantly (p= 0.0635 ; p= 0.0737) (Figure 1) Conclusion. In this small retrospective analysis, we observed an impact of toxicities related to L-ASPA on the PFS and the OS of patients with extra-nodal NK/T lymphoma. The identification of the risk factors associated to these toxicities needs to analyze large cohorts of prospective trials. Figure 1 Figure 1. Disclosures Brice: Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Seattle Genetics: Research Funding; Roche: Honoraria; Gilead: Honoraria; Bristol Myers-Squibb: Honoraria. Thieblemont:Roche: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 2860 Introduction. Histological lymphoma diagnosis of adult patients with bulky mediastinal mass is either HL or PMBL, two distinct diseases with a specific outcome. PET interpretation is often difficult for mediastinal lymphoma because of the volume of the tumor and the presence of blood pool. No specific criteria for interpretation of interim-PET have yet been defined in this clinical entity. The purpose of this study was to investigate the prognostic value of qualitative and semiquantitative evaluations of interim-PET in mediastinal lymphoma. Methods. We retrospectively included 72 patients with either HL (n=48) or PMBL (n=24), previously untreated, aged under 60 at diagnosis and who underwent at least one interim-PET evaluation. Patients with sub-diaphragmatic or medullar localisations of lymphoma were excluded. All PET scans were reviewed. Qualitative evaluation included global visual evaluation (GVE) (positive or negative) and 5 points-scale (5PS). Semiquantitative evaluation consisted in maximum standardized uptake value (SUVmax) and SUVmax reduction between the baseline PET (PET0) and the evaluation performed after two (PET2) or four (PET4) cycles of chemotherapy. Prognostic impact was evaluated on the event-free survival (EFS), defined as disease progression/first relapse (n=18) or death (n=2). ROC (Receiver Operating Characteristic) curve was used to assess the value of SUVmax reduction in discriminating future deaths or relapses, based on area under the curve (AUC). The “best“ cut-off that provides both the lowest false positive and the lowest false negative rates was computed. Results. Median age was 29 (24 - 35), 60% male. Tumoral mass was more than 7.5 cm in 70% of the patients, and M/T ratio〉= 0.35 in 79%. Median SUVmax at baseline, PET2 and PET4 were 12.8 (4.1;33.2), 1.9 (1.7;3.1), and 2.4 (1.7;3.1), respectively. With a median follow-up at 24 months, 2-year event-free survival (EFS) was 67%, without significant difference between HL and PMBL (p=0.98). Except for ECOG performance status in PMBL, neither clinical nor biological feature was predictive for EFS. Using GVE, a negative PET2 (n=36/59) and PET4 (n=24/34), were achieved in 61% and 71%, respectively. GVE and 5PS have a significant negative predictive value (NPV) at PET2 (HR=3.2, 95%CI: 1.2–8.2; p=0.012, and HR=1.9, 95%CI: 1.1–3.3, p=0.01) and at PET4 (HR=13.9, 95%CI: 3.5–55; p=0.0001, and 2.6, 95%CI: 1.5–4.7, p=0.001 respectively), with a 2-year estimated EFS of 69% for PET2-negative patients versus 51% for PET2-positive patients (p=0.012), and of 86% for PET4-negative patients versus 20% for PET4-positive patients (p=0.001). An optimal cut-off of 81% SUVmax reduction from PET0 to PET2 or PET4 yielded a 2-year estimated EFS of 70% in patients with reduction of more than 81%, versus 47% in those with reduction of 81% or less (p=0.004). In the HL subgroup, GVE and SUVmax reduction higher than 81% at PET2 (p=0.0001, p=0.015, respectively) and PET4 (p=0.004, p=0.015, respectively) showed significant prognostic values for EFS. In the PMBL subgroup, neither qualitative nor semiquantitative evaluation at PET2 was predictive for EFS. At PET4, GVE and 5PS were strongly predictive for EFS (p=0.005, p=0.0001). Patients with SUVmax reduction higher than 81% between PET0 and PET4 reached a 67% 2-year EFS, while patients with lower SUVmax reduction had only a 33% 2-year EFS (p=0.13). Conclusion. The cut-off value of SUVmax reduction estimated for predicting EFS with best accuracy in mediastinal lymphoma was 81%. Although the SUV semiquantification helps to reduce the number of false positives, visual global analysis had a significant negative predictive value in interim-PET in mediastinal lymphoma, with a possible very early prediction, as early as PET2 in HL, and a better prediction at PET4 than PET2 in PMBL. Disclosures: No relevant conflicts of interest to declare.

Description: Early identification of ultra-risk diffuse large B-cell lymphoma (DLBCL) patients is needed to aid stratification to innovative treatment. Previous studies suggested high baseline total metabolic tumor volume (TMTV) negatively impacts survival of DLBCL patients. We analyzed the prognostic impact of TMTV and prognostic indices in DLBCL patients, aged 60 to 80 years, from the phase 3 REMARC study that randomized responding patients to R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) into maintenance lenalidomide or placebo. TMTV was computed on baseline positron emission tomography/computed tomography using the 41% maximum standardized uptake value method; the optimal TMTV cutoff for progression-free (PFS) and overall survival (OS) was determined and confirmed by a training validation method. There were 301 out of 650 evaluable patients, including 192 patients classified as germinal center B-cell–like (GCB)/non-GCB and MYC/BCL2 expressor. Median baseline TMTV was 238 cm3; optimal TMTV cutoff was 220 cm3. Patients with high vs low TMTV showed worse/higher Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, stage III or IV disease, 〉1 extranodal site, elevated lactate dehydrogenase, International Prognostic Index (IPI) 3-5, and age-adjusted IPI 2-3. High vs low TMTV significantly impacted PFS and OS, independent of maintenance treatment. Although the GCB/non-GCB profile and MYC expression did not correlate with TMTV/survival, BCL2 〉70% impacted PFS and could be stratified by TMTV. Multivariate analysis identified baseline TMTV and ECOG PS as independently associated with PFS and OS. Even in responding patients, after R-CHOP, high baseline TMTV was a strong prognosticator of inferior PFS and OS. Moreover, TMTV combined with ECOG PS may identify an ultra-risk DLBCL population. This trial was registered at www.clinicaltrials.gov as #NCT01122472.

Description: Background. Anti-CD19 Chimeric Antigen Receptor (CAR) T-cells is a major therapeutic advance in the management of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). However, some patients will experience progression or relapse after infusion. Treatment of these relapses or progressions is not standardized and is usually based on strategies that will avoid the destruction of the CAR T-cells, such as immuno-oncology drugs. Lenalidomide is reported to activate CD8 T cells, inhibit regulatory T cells and restore T-cell immune synapse. We report here our experience of Lenalidomide in the treatment of progression or relapse after CAR T-cells infusion. Methods. Between June 2018 and July 2020, 111 patients with R/R DBLCL were treated with commercialized anti-CD19 CAR T-cells, axicabtagene ciloleucel (axi-cel yescarta) (n=60) or tisagenlecleucel (Tisa-cel kymriah) (n=51). Relapse and progression after CAR T-cells was defined based on the Cheson 2014 criteria. Efficacy of the treatment proposed at time of relapse post-CAR T-cells was assessed by CT scan and 18FDG-PET after the 1st cycle and at the end of treatment. CAR-T expansion was regularly monitored in blood by flow cytometry. Results. In the whole cohort, the clinical characteristic was a median age at 61.9 (range 23 to 77), male n=73 (66%). Histology subtypes were DLBCL (n=90) (including GC n=39 and non-GC n=37), PMBL (n=6), Tr FL (n=15). 85 (76.6%) patients presented a primary refractory lymphoma. IPI included 30 low risk, 23 low-intermediate, 23 high-intermediate and 14 high risk. The median number of lines of treatment before CAR T cells infusion was 3 (IQR, 2 to 4) ranging from 1 to 9. At time of infusion, median total metabolic tumor volume (TMTV) was 52.4 (IQR, 12.1 to 170.1), ranging from 1.44 to 4247. Fifty-nine patients failed after Tisa-cel (n=33) of Axi-cel (n=26) infusion. Failure occurred after CAR T-cell within a median time of 6 months; 16 (27%) of the failures occurred before day 15 (D15), 27 (45.8%) during the first month after infusion (

Description: Background. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is currently considered as the standard of care for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). However, three-year progression-free survival (PFS) and overall survival (OS) rates remain at 60% and 70%, respectively. We recently reported a new tool to help the early identification of ultra-high risk DLBCL patients1. This tool was identified in a cohort of 301 patients included in the REMARC study, responders to R-CHOP, and was based on a combination of 2 factors at baseline: 1/ total metabolic tumor volume (TMTV) above 220cm3 measured on baseline 18FDG-PET and 2/ elevated ECOG PS ≥2. Here, we validated this combination in multiple cohorts including two large clinical trials and in real world. Methods: We evaluated the combination TMTV-PS in a series of 2306 patients with DLBCL including patients treated in clinical trials in Europe and the United States; PETAL (n= 510) and GOYA (n=1315) and 481 patients treated in Real world (RW) across multiple centers in Europe (France, Poland, Portugal, UK). All patients were treated with a combination of immuno-chemotherapy with curative intent (Rituximab (R) or Obinutuzumab (0)-CHOP (R-CHOP n= 70%%, O-CHOP n= 29 %, and intensified regimen n=1%). Patients in PETAL were treated by a PET-guided strategy. Associations of TMTV and ECOG PS at baseline were explored with the International Prognostic Index (IPI) and outcome. Results. For the PETAL, GOYA, and RW series, the median age was 62 (18-80), 62 (18-86), and 65 (17-92), and 55%, 58%, 60%, were 〉 60y respectively. ECOG PS〉2 was present in 11%, 12%, 23% of the patients; IPI 3-5 in 38%, 44%, 51%; TMTV〉220 in 45%, 61%, 44%, respectively. The combination of TMTV〉220cm3 and ECOG PS〉2 defined in PETAL, GOYA, and RW, patients with no risk factor representing 53%, 37% and 49% of the patients, one risk factor (either TMTV〉 220cm3 or ECOG PS〉2) representing 38%, 53.5%, 35% of the patients, and two risk factors representing 9%, 10%, and 16%, respectively. Patients with 2 risk factors had a significantly worse PFS than patients with 0 or 1 risk factor in the PETAL, GOYA and RW series, HR=3.32 (95% CL: 2.0-5.5); HR=2.68 (95% CL: 2.0-3.6), HR=4.06 (95% CL : 2.7-6.1), respectively. Overall survival was also significantly worse in patients with 2 risk factors than patients with 0 or 1 risk factor, HR=3.85 (95% CL: 2.2-6.8); HR=3.16 (95% CL: 2.2-4.5), HR=5.23 (95% CL: 3.4-8.1), respectively. The combination of TMTV-PS performed better than IPI with a positive C-Index for PFS and OS across all the series, PETAL, GOYA, and RW (figure 1) Conclusion. The combination of TMTV and ECOG PS improves risk stratification for patients with DLBCL treated in frontline by standard treatment or intensified immuno-chemotherapy. This observation meets an unmet need for early and better identification of ultra-high risk DLBCL patients. Disclosures Thieblemont: Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Hospira: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Bayer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Dührsen:Gilead/Kite: Consultancy, Honoraria; Alexion: Honoraria; CPT: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: travel, accomodations, expenses; Janssen: Consultancy, Honoraria, Other: travel, accomodations, expenses. Vitolo:Roche: Honoraria, Other: travel, accomodations, expenses; Jansen: Honoraria. Zaucha:Cellgene: Other: travel, accomodations, expenses; Abbvie: Honoraria; Sandoz: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses; Takeda: Consultancy, Honoraria, Other: travel, accomodations, expenses; BMS: Consultancy; Novartis: Consultancy. Maria:Gilead: Consultancy, Other: travel, accomodations, expenses, Research Funding; Janssen: Consultancy, Other: travel, accomodations, expenses; MSD: Consultancy; BMS: Consultancy; Roche: Consultancy, Other: travel, accomodations, expenses; Abbvie: Consultancy, Other: travel, accomodations, expenses. Decazes:Bayer: Other: travel, accomodations, expenses. Tilly:BMS: Honoraria. Casasnovas:MSD: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Amgen: Consultancy, Honoraria. Hüttmann:University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Lead Discovery Center GmbH: Consultancy; Gilead: Honoraria; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Seattle Genetics: Research Funding; Roche: Other: Travel expenses. Schmitz:Abbvie: Other: travel. Paulson:F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Meignan:ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).