ALBERT

Description: Introduction: There is no standard treatment of refractory or relapsed (R/R) patients (pts) with DLBCL ineligible for autologous stem-cell transplantation (ASCT). However, R-GemOx is widely used in these circumstances. We here report the results of a retrospective analysis of a cohort of patient treated in two academic centers in France. The main objectives were to evaluate the activity and safety profile of this regimen in a large series of R/R DLBCL pts in a real life setting. Methods: Patients selected had to have de novo or transformed DLBCL, R/R after at least one line of treatment containing doxorubicin and rituximab, to be ineligible for ASCT and to have received at least one cycle of R-GEMOX. Rituximab 375 mg/m2 was administered on D1, gemcitabine 1000 mg/m2 on D2 and oxaliplatin 100 mg/m2 on D2 as previously described (Mounier N. et al. Haematologica 2013; 98:1726-31). Cycles were given every 2 weeks and 8 cycles were planned if at least a partial response (PR) was obtained after 4 cycles. Results: Between May 2002 and May 2017, 196 pts were treated. Baseline characteristics were: median age: 72 y (range, 24-89), international prognostic index (IPI) 3-5: 63%, refractory state to last treatment (tx): 42%, history of indolent lymphoma: 45%, prior ASCT: 16%. The median number of previous line was 1 (range 1-7) with 112 pts having received R-GemOx in second line. One hundred and thirty-six pts received at least 4 cycles, 86 pts completed 6 cycles and 61 pts 8 cycles. After 4 cycles, the overall response rate (ORR) according to IWC (Cheson 1999 or 2007) was 54 % and the complete response (CR) rate was 23 %. At the end of treatment, the ORR and CR rates were 38 % and 33 %, respectively. With a median follow-up of 22 months, median (m) progression-free survival (PFS) and overall survival (OS) were 5 and 10 months (mo), respectively. mOS was significantly longer in case of prior history of indolent lymphoma (21 vs 8 mo, p 〈 0.001), age

Description: Background Primary Central Nervous System Lymphoma (PCNSL) are rare and aggressive primary brain tumors. Histological diagnosis can be difficult at initial stages or at relapse due to deep brain structure involvement. Finding a minimally invasive biomarker aiding the diagnosis remains an unsolved question. Plasma Cell-Free DNA (cfDNA) seems to have shown its diagnostic and prognostic value in nodal Diffuse Large B Cell Lymphomas (DLBCL) [Roschewski et al, Lancet Oncology, 2015; Kurtz et al, Blood, 2015]. Our main objective was to demonstrate that targeted sequencing of cfDNA in plasma at time of diagnosis could identify PCNSL somatic mutations. Methods 30 immuno-competent patients suffering from newly diagnosed PCNSL, without any extranevraxic lesions, were enrolled from 2008 to 2014. Tumor tissues and plasma samples were collected at the time of diagnosis and frozen until use. High throughput sequencing was performed on primitive tumors using a panel of 34 genes relevant to lymphomagenesis, as previously reported [Dubois et al, Oncotarget, 2015; Bohers et al, Haematologica, 2015]. We next performed patient-specific targeted sequencing of identified somatic mutations in cfDNA. The detection sensitivity threshold was set at 1% for all SNVs, except for MYD88 L265P, which was set at 0.1%. The primary endpoint was the proportion of patients having at least one somatic mutation found in the plasma. Results Among 24 available plasmas, 15 patients (63%) had at least one detected somatic mutation in cfDNA. All plasmas had detectable cfDNA (mean concentration 1.6 ng/µL). No correlation was found between tumor volume and cfDNA concentration (R squared coefficient 0.01). Regarding the whole sequenced cohort (n=30) 21 (70%) were classified as nonGC subtype, 8 (27%) as GC subtype and 1 patient (3%) as unclassifiable, according to the Hans algorithm. 29 tumors had at least one somatic mutation, mainly nonsynonymous single nucleotide variants (SNV). The NF-kB pathway was the most affected by mutations: MYD88 (n=23, 77%), PIM1 (n=11, 37%), TNFAIP3 (n=6, 20%), IRF4 (n=3, 10%), CARD11 (n=3, 10%) and PRDM1 (n=3, 10%). Among the 23 tumors harboring a MYD88 mutation, the L265P variant was the most frequent (20 patients, 67%); mean tumor variant allele frequency was 46% [min 8%, max 91%]. One tumor harbored a single MYD88 L265P mutation with no other detectable abnormality. Among patients with both available plasma and a somatic MYD88 L265P mutation in the tumor, 15 patients (88%) had an identifiable L265P variant in cfDNA, with a mean variant allele frequency of 4% [min 0.1%, max 28%]. PIM1 and TNFAIP3 SNVs were also detected in cfDNA for respectively two and one patient. The second most affected pathway was the apoptotic pathway: genes affected by mutations included GNA13 (n=7, 23%), TP53 (n=2, 7%), MYC (n=1, 3%), CDKN2A (n=2, 7%) and BCL2 (n=1, 3%). The B Cell Receptor (BCR) pathway was also affected, mainly due to mutations targeting CD79B (n=10, 33%) and ITPKB (n=3, 10%) mutations. 8 tumors (27%) harbored a dual alteration affecting MYD88 and CD79B. One tumor of the GC subtype had one EZH2 SNV (Y646H), but the mutation was not found in cfDNA. There was no significant difference in overall survival (OS) between patients with and without mutations detected in cfDNA: mean OS 27 months versus 18 months (HR 0.6; IC95% [0.2 - 1.6], p value 0.3). Tumor gene copy number variations were detected in 29/30 patients with either homo or heterozygous deletions or copy gains. CDKN2A/2B deletions were detected in 23 cases (77%). Conclusion To our knowledge this is the first study that provides evidence that somatic mutations can be detected in cfDNA in patients suffering from PCNSL, therefore constituting a minimally invasive tool helping for diagnosis. Further studies are now required to improve prognosis and predictive values of this new promising procedure for PCNSL patient care. Disclosures No relevant conflicts of interest to declare.

Description: Background and aim of the study Primary mediastinal B-cell lymphoma (PMBL) is an entity of aggressive B-cell lymphoma that is clinically and biologically distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We recently detected by Whole exome sequencing a recurrent point mutation in the XPO1 (exportin 1) gene (also referred to as chromosome region maintenance 1; CRM1), which resulted in the Glu571Lys (p.E571K) missense substitution in 2 refractory/relapsed PMBL (Dubois et al., ICML 2015; Mareschal et al. AACR 2015). XPO1 is a member of the Karyopherin-b superfamily of nuclear transport proteins. XPO1 mediates the nuclear export of numerous RNAs and cellular regulatory proteins, including tumor suppressor proteins. This mutation is in the hydrophobic groove of XPO1 that binds to the leucine-rich nuclear export signal (NES) of cargo proteins. In this study, we investigated the prevalence, specificity, and biological / clinical relevance of XPO1 mutations in PMBL. Patients and methods High-throughput targeted or Sanger sequencing of 117 PMBL patients and 3 PMBL cell lines were performed. PMBL cases were defined either molecularly by gene expression profile (mPMBL cohort) or by standard histological method (hPMBL cohort) and enrolled in various LYSA (LYmphoma Study Association) clinical trials. To assess the frequency and specificity of XPO1 mutations, cases of classical Hodgkin lymphoma (cHL) and primary mediastinal grey zone lymphoma (MGZL) were analysed. Cell experiments were performed to assess the impact of the E571 mutation on the activity of selective inhibitor of nuclear export (SINE) molecules. Results XPO1 mutations were present in 28/117 (24%) PMBL cases but were rare in cHL cases (1/19, 5%) and absent from MGZL cases (0/20). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in PMBL cases defined by gene expression profiling (n = 32), as compared to hPMBL cases (n = 85, 13%). No difference in age, International Prognostic Index (IPI) or bulky mass was observed between the PMBL patients harboring mutant and wild-type XPO1 in the overall cohort whereas a female predominance was noticed in the mPMBL cohort. Based on a median follow-up duration of 42 months, XPO1 mutant patients exhibited significantly decreased PFS (3y PFS = 74% [CI95% 55-100]) compared to wild-type patients (3y PFS = 94% [CI95% 83-100], p=0.049) in the mPMBL cohort. In 4/4 tested cases, the E571K variant was also detected in cell-free circulating plasmatic DNA, suggesting that the mutation can be used as a biomarker at the time of diagnosis and during follow-up. Importantly, the E571K variant was detected as a heterozygous mutation in MedB-1, a PMBL-derived cell line, whereas the two other PMBL cell lines tested, Karpas1106 and U-2940, did not display any variants in XPO1 exon 15. KPT-185, the SINE compound that blocks XPO1-dependent nuclear export, induced a dose-dependent decrease in cell proliferation and increased cell death in the PMBL cell lines harbouring wild type or mutated alleles. To test directly if XPO1 mutation from E571 to E571K alters XPO1 inhibition by SINE compounds, the mutated protein was tested in vitro. The E571XPO1 mutated allele was transiently transfected into osteosarcoma U2OS cells which stably express the fluorescently labelled XPO1 cargo REV. Cells were treated with the clinical SINE compound selinexor, which is currently in phase I/II clinical trials and nuclear localization of REV-GFP was analysed in red transfected cells. The results showed that the nuclear export of the mutated XPO1 protein was inhibited by selinexor similarly to the wild-type XPO1 protein (Figure 1). Conclusion Although the oncogenic properties of XPO1 mutations remain to be determined, their recurrent selection in PMBL strongly supports their involvement in the pathogenesis of this curable aggressive B-cell lymphoma. XPO1 mutations were primarily observed in young female patients who displayed a typical PMBL molecular signature. The E571K XPO1 mutation represents a novel hallmark of PMBL but does not seem to interfere with SINE activity. Rev-GFP (green fluorescent) expressing U2OS cells were transfected with wild type XPO1-RFP (red fluorescent protein), XPO1-C528S-RFP, XPO1-E571K-mCherry, and XPO1-E571G-mCherry. The cells were then treated with 1µM KPT-330 for 8 hours. Figure 1. Rev-GFP expressing U2OS cells transfected with XPO1 variants. Figure 1. Rev-GFP expressing U2OS cells transfected with XPO1 variants. Disclosures Landesman: Karyopharm Therapeutics: Employment. Senapedis:Karyopharm Therapeutics, Inc.: Employment, Patents & Royalties. Argueta:Karyopharm Therapeutics: Employment. Milpied:Celgene: Honoraria, Research Funding.

Description: In acute leukemia, recurrent chromosomal translocations which result in the fusion of two genes are frequent. Some of these markers have a well established prognostic and therapeutic impact and are routinely screened at diagnosis by cytogenetics and RT-PCR. Yet, due to the limitations of these methods, only a few among the dozens of known rearrangements are systematically tested. Many abnormalities which could provide important clinical information thus remain ignored, mainly due to the impossibility of performing a cost effective multi-targeted screening. To overcome this obstacle, we have developed a simple and parsimonious assay which allows a reliable detection of dozens of fusion genes in only a few hours. Our assay was designed to screen simultaneously more than 50 translocations involving 70 genes, recurrent in acute myeloid (AML), acute lymphoid (ALL) and chronic myeloid (CML) leukemia. cDNA samples obtained from leukemic cells are first incubated with a mix of oligonucleotides probes which are complementary to the ends of the exons, at the abnormal junctions on the fusion mRNAs (Figure). For most genes, different probes were designed to detect different transcripts resulting from alternative genomic breakpoints (for example on exons 1, 13, 14 and 19 for BCR, and on exons 2 and 3 for ABL). The mix we created thus regroups more than 150 probes and targets more than 400 different fusion transcripts. All left probes have a common tail (T1) at their 5' ends, all right probes a common tail (T2) at their 3' ends. Additional probes were also included to detect the most frequent mutations of NPM1 (A, B, D). If one translocation is present in the sample, two probes hybridize side to side on the fusion cDNA. A DNA ligase is next used to create a covalent link between these probes, allowing their amplification by PCR with the T1 and T2 primers. If a PCR product is amplified, the two partners are identified by sequencing analysis. To test this method, we applied it to a retrospective series of 430 patients, (252 AML and 178 childhood ALL). In B-ALL (147 cases), all 33 ETV6-RUNX1, 6 BCR-ABL and 5 TCF3-PBX1 as well as 6 MLL rearrangements (3 AF4; 1 ENL, 1 AF9 and 1 AFF4) identified at diagnosis by conventional methods were detected, as well as 5 previously unnoticed P2RY8-CRLF2 junctions. We only failed to detect one MLL-AF4 fusion detected by cytogenetics but not by RT-PCR, probably due to the poor quality of the RNA. Further analysis of 10 MLL-AF4 positive adult ALL patients allowed the correct identification of this fusion in all cases. In T-ALL (31 cases), we detected 6 known (4 SIL-TAL, 2 CALM-AF10) and 5 previously undetected fusions (2 NUP214-ABL, 1 MLL-ENL, 1 ETV6-ABL, and a new PLZF-ABL junction). In AML, we detected 86 fusions: 23 PML-RARA, 2 PLZF-RARA, 18 CBFB-MYH11, 12 RUNX1-RUNX1T1, 4 NUP98-NSD1, 2 BCR-ABL, 1 DEK-NUP214, 1 CALM-AF10, 1 MOZ-CBP, 22 MLL rearrangements (13 PTD, 3 AF9, 2 AF6, 1 AF10, 1 ENL, 1 AF1Q and 1 MAPRE) and 44 NPM1 mutations. Two PML-RARA cases, one with a BCR2 breakpoint (not included in our design), one weakly positive by RT-PCR but negative by cytogenetics, two t(11;17) validated by FISH but negative by RT-PCR, and one NPM1J mutation (not included in our assay) were not detected. Importantly, 20 translocations in this series, including 14 MLL fusions and a cytogenetically cryptic t(8;21) had not been identified at diagnosis. Furthermore, all these new abnormalities (in AML and ALL) could be confirmed by conventional RT-PCR and sequencing analysis, demonstrating the specificity of the method. In the whole cohort of 430 patients, the three methods thus detected 157 fusions. 85 (54.1%) and 112 (71.3%) had been detected at diagnosis by cytogenetics and RT-PCR respectively, and 152 (96.8%) by our assay. Two were revealed only by cytogenetics, one only by RT-PCR and 30 only by our method. In conclusion, we have developed a simple multiplexed assay which can reveal a very large number of recurrent gene fusions in leukemia. Its short turn-around time (we repeatedly tested up to 40 patients in parallel and the results can be obtained in less than one day) and low cost (only one PCR module, one pyrosequencer and basic molecular biology reagents are needed) make it particularly suitable for a daily practice. Its capacity to detect many abnormalities which are almost never tested in daily practice could provide many important diagnosis and prognosis information, and enable the stratification of patients in prospective clinical trials. Figure 1 Figure 1. Disclosures Ruminy: Centre Henri Becquerel: Patents & Royalties. Marchand:Centre Henri Becquerel: Patents & Royalties.

Description: Introduction: The autologous anti-CD19 chimeric antigen receptor (CD19 CAR) T-cells demonstrated significant clinical benefits and a manageable safety profile in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), with an ORR of 52-83% and CR of 40-58% in the 3 pivotal clinical trials (ZUMA-1, TRANSCEND-NHL-001, JULIET), leading to a rapid approval in third line R/R DLBCL in Europe and in USA. The CD19 CAR T-cells Axicabtagene and Tisagenlecleucel have been approved in France since June 2018 for patients with DLBCL, primary mediastinal B-cell lymphomas (PMBL) and transformed FL (tFL), recurrent or refractory after 〉 2 systemic therapy lines. However, all patients are not deemed eligible for such therapy. Here we describe the characteristics of the non-eligible patients and the causes of non-eligibility for CD19 CAR T-cells at our center. Methods: We performed a retrospective analysis of all patients for whom our center was contacted for potential eligibility to CD19 CAR T-cells. Upon each request, a screening form was completed by the referring hospital to validate the indication (DLBCL, PMBL or tFL; recurrent or refractory to 〉 2 systemic therapy lines) and the absence of contra-indications (CNS involvement (MRI mandatory), active infection). The patient was then evaluated in our hospital to check the predetermined eligibility criteria: age, comorbidities, LVEF 〉 45%, no pericarditis or cardiogram abnormality, creatinine clearance 〉 60 mL/min, ALT/AST 〈 2.5 N, total bilirubin 〈 1.5 mg/dL, no pleural effusion, SpO2 〉 92% without oxygen, lymphocytes 〉 100/µL, no rapid progressive disease (compressive mass, PS 〉 2 or rapid increase of LDH), or no active neurological/auto-immune disease. In case of severe comorbidities or age〉 70, patient's frailty index was assessed by an ICU physician. Eligibility was then finally validated by our local board through a careful case-by-case analysis. Results: Between June 2018 and July 31, 2019, 221 requests were analyzed. Evaluation is still ongoing for 6 patients (3%). 80/215 patients (37%) were deemed eligible for CAR T-cells, 58 patients (27%) were excluded before any visit at the expert hospital because of histology other than DLBCL, PMBL and tFL (n=30: non-transformed FL 9, transformed SLL/CLL 7, transformed Waldenström 3, transformed MZL 3, MZL 2, primary CNS lymphoma 2, SLL/CLL 1, HL 1, lymphoblastic lymphoma 1, CD19- 1), 〈 2 previous lines (n=7), CNS involvement (n=7), administrative reason (n=14). The remaining 77 patients (36%) were deemed non-eligible for CAR T-cells after the first visit. Median age was 59 years (range 18-86, 41% ≥ 65 years), 68% were male. There were 62, 4 and 2 patients with DLBCL, PMBL and tFL, respectively. Median number of prior lines was 3 (range 2-11, 43% 〉 3 lines), 86% of patients presented with a primary refractory disease. Nine patients were with a refractory disease despite stem cell transplantation (SCT, 5 autologous, 3 allogeneic and 1 both). Considering these 77 patients, 12 (16%) had 2 concomitant causes of non-eligibility. Overall, the two main causes of non-eligibility were rapid disease progression (n=49) and major frailty (n=23), including 10 patients with 11 severe organ dysfunctions [5 cardiac, 3 kidney, 1 liver, 1 respiratory and 1 heavy engine handicap]. Replicative viral infections (n=4) constituted also an important cause of frailty: HIV (1), HBV (2), HBV + HCV (1). Two patients had a solid organ transplantation requiring immunosuppressive drugs. Advanced neurological diseases (n=4) included: extrapyramidal syndrome (3), advanced multiple sclerosis (1). Active autoimmune diseases were a cause of frailty for 2 patients: thyroiditis (1), periodic fever (1). In one patient, the screening evaluation showed a concomitant malignancy. Other causes of non-eligibility were found in 17 patients: complete remission after the salvage therapy (n=7), age 〉 80 (n=4), severe thrombocytopenia 〈 20 G/L (n=2), no slot available (n=1), patient refusal (n=3). Outcomes of the non-eligible patients (alternative treatments, survival) will be presented at the meeting. Conclusion: In this pioneering experience, 37% of patients in whom a CAR T-cell request is made are ultimately deemed eligible for the therapy. Other patients are either rapidly excluded based on lack of CAR T-cells indications (27%), or deemed non-eligible because of failure to control the disease / major frailty (36%). Disclosures Paillassa: Janssen: Other: Bibliography board with young hematologists. Di Blasi:Novartis: Honoraria. Casasnovas:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau. Gyan:Pfizer: Honoraria. Haioun:novartis: Honoraria; celgene: Honoraria; roche: Consultancy; celgene: Consultancy; gilead: Consultancy; takeda: Consultancy; janssen cilag: Consultancy; amgen: Honoraria; servier: Honoraria. Thieblemont:Roche: Honoraria, Research Funding; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Novartis: Honoraria.

Description: Background Peripheral T-cell lymphoma (PTCL) is a heterogeneous and accounts for approximately 10% of all lymphomas. Outcome of relapse/refractory (R/R) PTCL is poor with median progression-free survival (PFS) and overall survival (OS) of 3 and 6 months in the absence of stem-cell transplantation (SCT). [Mak, JCO, 2013]. Brentuximab vedotin (BV) monotherapy is approved for R/R systemic anaplastic large cell-lymphoma (ALCL) based on 86% overall response rate (ORR) and 57% complete remission (CR). [Pro, JCO, 2012]. In other CD30-positive (CD30+) R/R PTCL, the ORR of BV is 41%. Gemcitabine (G) used as monotherapy in control arm in the randomized phase 3 LUMIERE trial, provided ORR and CR rates of 35 and 22% respectively. [O'Connor, JCO, 2019]. Considering these results we designed a phase 2 study for R/R CD30+ PTCL combining G and BV with the primary end point to increase the ORR by 15%, compared to G monotherapy. Patients (pts) and Methods: Pts with histologically confirmed CD30+ (≥5%) PTCL who failed or were refractory to 1-3 prior lines of systemic therapy, with measurable disease and ECOG performance status 〈 3 were eligible. Pts received an induction of 4 cycles of G-BV (28-days cycles; G: 1000 mg/m² at D1 and D15 plus BV: 1.8 mg/kg at D8). Pts with CR or partial remission (PR) and non-eligible for SCT, received BV maintenance 1.8 mg/kg at D1 (21-days cycles) up to 12 cycles. The primary endpoint was the ORR (CR + PR) according to Lugano criteria based on CT-scan. Secondary objectives included tolerance and safety, DOR, PFS, OS and impact of BV maintenance. Eligible pts were censored at time of SCT. (NCT03496779). Results: From April 2018 to October 2019, 71 pts were included. Pathology central review according to WHO 2017 criteria, so far available for 50 patients, confirmed angioimmunoblastic T-cell lymphoma (AITL) (22 ; 31%); nodal PTCL-TFH (5 ; 7%); PTCL-NOS (5 ; 7%); ALK- ALCL (10 ; 14.1%) ; ALK+ ALCL (4 ; 5.6%), Enteropathy associated T-cell lymphoma (EATL) (2 ; 2.8%); unclassified PTCL (2 ; 2.8%). There were 47 male and 24 female with a median age of 66 years (20-79) and 17 pts were 〉 75 years. Median time from diagnosis to enrolment was 9.4 months (range, 6-21). Sixty-five pts (91.6%) presented with stage III-IV. The number of prior lines of therapy were 1 (57 pts), 2 (11 pts) or 3 (3 pts), all pts had received previous CHOP-like chemotherapy, 11 pts previous autologous SCT, 5 pts epigenetic modifiers and 39.4% were refractory to their last line of treatment prior to inclusion. The cut-off date of this analysis was 01/31/2020. The 4 cycles of G-BV induction were completed in 45 pts (63%). The reasons for early discontinuation were progression (21 pts), death (3 pts) or adverse event (2 pts). In intention-to-treat analysis, the ORR at the end of induction (EOI) was 47.9% including CR (14 pts; 19.7%), PR (20 pts; 28.2%). PET performed in all patients reaching EOI showed overall and complete metabolic responses in 45.1 and 23.9%, respectively. During G-BV induction 58 pts (81.7%) had at least one G 〉 3 adverse event (AE) including neutropenia (67.2%), thrombopenia (17.2%), infections (15.5%), peripheral neuropathy (PN) (5.2%) and cardiac event (5.2%). Overall PN of any grade was recorded in 8/71 patients (11%) during G-BV induction and caused BV withdrawal in one case. Among the 34 responding pts after EOI, 27 pts began BV maintenance and 7 pts remain on maintenance at cut-off date. Eight pts were removed from the study due to SCT eligibility, either after the 4 GBV induction (4 pts) or after 1 or 2 maintenance BV cycles (4 pts). With a median follow-up (FU) of 9.5 (0.5-19.4) months, median PFS is 4.5 months (95%CI [3.5 - 10]) and median OS is 12 months (95%CI [8.6 - NR]). Among the 34 patients in PR/CR after induction, the duration of response (DOR) is 12.8 months (95%CI [10.3 - NR]). At last FU were recorded 32 deaths. Disease status at time of death was PD (25 pts), CR (1 pt) NE or missing (6 pts). Conclusion: The addition of BV to G increases the overall response rate by 15% in the treatment of R/R CD30+ PTCL. OS data are encouraging for this overall R/R patient population but PFS is overall short and a longer FU is mandatory. Especially the DOR of pts achieving CR or PR after 4 cycles of G-BV exceeds 1 year on BV maintenance. This combination is generally well tolerated and this study suggests that G-BV combination could be an interesting alternative for R/R CD30+ PTCL. Disclosures Tournilhac: Janssen: Consultancy, Honoraria, Other: Travel grant; INNATE Pharma: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria, Other: Travel Grant; ABBVIE: Consultancy, Honoraria, Other: Travle grant; Takeda: Consultancy, Honoraria, Other: Travel grant. Laribi:novartis: Honoraria, Research Funding; amgen: Research Funding; abbvie: Honoraria, Research Funding; takeda: Research Funding. Ysebaert:AbbVie: Consultancy; Roche: Consultancy; Janssen: Consultancy. Guidez:BMS: Honoraria; TAKEDA: Honoraria; Service Hématologie et Thérapie cellulaire CHU POITIERS: Current Employment; AMGEN: Honoraria; CELGENE: Honoraria; JANSEN: Honoraria. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. André:Celgene: Other, Research Funding; Takeda: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Johnson & Johnson: Research Funding; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy; Seattle Genetics: Consultancy. Dupuis:Henri Mondor University Hospital Creteil France: Current Employment. Thieblemont:Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding; Cellectis: Speakers Bureau. Bachy:Beigene: Membership on an entity's Board of Directors or advisory committees; Roche, Gilead: Consultancy; Amgen: Research Funding; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria. Morschhauser:Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Servier: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Feugier:janssen: Consultancy, Honoraria, Research Funding; gilead: Consultancy, Honoraria, Research Funding; roche: Consultancy, Honoraria, Research Funding; astrazeneca: Consultancy, Honoraria, Research Funding; abbvie: Consultancy, Honoraria, Research Funding. Cartron:F. Hoffmann-La Roche: Consultancy, Honoraria; Abbvie: Honoraria; Jansen: Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Honoraria; Gilead: Honoraria. Camus:ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); JANSSEN: Honoraria; AMGEN: Honoraria; PFIZER: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Sibon:takeda france: Consultancy. Snauwaert:roche: Other: travel; janssen: Other: travel; abbvie: Other. Delarue:BMS: Other: stock options ; Celgene/BMS: Current Employment. De Leval:Abbvie: Honoraria; Lausanne University Hospital & Lausanne University Institute of Pathology: Current Employment; Roche Diagnostics: Honoraria; Lunaphore Technologies SA: Consultancy, Honoraria. Gaulard:CHU Henri Mondor, Assistance Publique-Hôpitaux de Paris: Current Employment; TAKEDA: Consultancy, Honoraria, Research Funding; INNATE PHARMA: Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).

Description: Introduction: Primary mediastinal B cell lymphoma (PMBL) is clinically and biologically distinct from the other subtypes of diffuse large B cell lymphoma (DLBCL), typically affecting young female patients (pts) with a bulky mediastinal mass. Standard treatment (TRT) is a combination of anti-CD20 antibody (Ab) and anthracycline-based chemotherapy. We aimed to compare patients' outcomes after CHOP delivered every 21 days (CHOP21) or 14 days (CHOP14) or ACVBP combined with anti-CD20 Ab in real life. Methods: All Pts treated in LYSA centers were eligible in this retrospective analysis. Inclusion criteria were as follow: age ≥18 years (yrs), newly diagnosed PMBL, TRT with CHOP or ACVBP plus anti-CD20 Ab between 2006 and 2017, and patient non-opposition statement. Primary endpoint was progression-free survival (PFS), secondary endpoints were: overall survival (OS), response rate (Lugano 2014) and total metabolic tumor volume (TMTV). Results: 313 pts were enrolled from 25 LYSA centers in France and Belgium. In all, median age at diagnosis was 32 (18-88) yrs. Majority of pts were female pts (60.7%) and presented at diagnosis with a good performance status (0-1: 81.8%), stage I-II (57.5%), elevated LDH (85%), Bulk〉10cm (58.5%) and low/low-intermediate aaIPI 0-1 (56.7%). Pts in the CHOP21 (n=57) group were older (median 40 yrs, vs 33 vs 29.5, p

Description: Background: Peripheral T-cell lymphoma (PTCL) is an aggressive form of non-Hodgkin lymphoma (NHL) that is typically associated with a poor prognosis. Romidepsin is a histone deacetylase inhibitor approved by the US Food and Drug Administration for patients with PTCL who have received at least 1 prior therapy (J Clin Oncol. 2012;30:631). Presented here is the final analysis of a phase III randomized study comparing romidepsin + cyclophosphamide, doxorubicin, vincristine, and prednisone (Ro-CHOP) with CHOP in patients with previously untreated PTCL. Methods: Ro-CHOP (NCT01796002) is a randomized multicenter phase III study in adult patients with previously untreated PTCL (i.e. nodal or extranodal entities including primary cutaneous non epidermotropic TCL, with the exclusion of ALK-positive anaplastic large cell lymphomas and EBV-positive extranodal NK/T-cell lymphomas). Diagnostic biopsies were centrally reviewed (94%), and patients were randomized based on International Prognostic Index (IPI) score at baseline (〈 2 vs ≥ 2), age (≤ 60 vs 〉 60 y), and histology type (nodal vs extranodal) to receive either Ro-CHOP or CHOP. Two-sided P-value from log-rank test stratified by all 3 stratification factors was used. All patients received CHOP in 3-week cycles for 6 cycles. Romidepsin, 12 mg/m2, was administered intravenously on days 1 and 8 of each 3-week cycle for 6 cycles (Lancet Haematol. 2015;2:e160), with dose reductions to 10 and 8 mg/m2 based on toxicity. The primary end point was progression-free survival (PFS) per Response Adjudication Committee assessment according to International Working Group 1999 criteria. Secondary end points included overall survival (OS), objective response rate (ORR), complete response (CR) + CR unconfirmed (CRu), and safety. Results: As of the December 13, 2019 cutoff date, 421 patients were included in the intention-to-treat population (Ro-CHOP, n = 211; and CHOP, n =210). Median age was 65 y (range, 25-81); 76 patients (18%) had ECOG PS of 2-3; 267 (63%) had Ann Arbor stage IV disease; and 342 (81%) had IPI score ≥ 2. At a median follow-up of 27.5 mo, the study did not meet its primary end point because Ro-CHOP did not show a statistically significant PFS improvement vs CHOP alone. Median PFS for Ro-CHOP vs CHOP was 12.0 mo (95% CI, 9.0-25.8) vs 10.2 mo (95% CI, 7.4-13.2), with a hazard ratio of 0.81 (95% CI, 0.63-1.04; P = 0.096). Median OS for Ro-CHOP vs CHOP was 51.8 mo (95% CI, 35.7-72.6) vs 42.9 mo (95% CI, 29.9-not evaluable). ORR of Ro-CHOP vs CHOP was 63% vs 60% with CR + CRu rates of 41% vs 37%. In the safety population (Ro-CHOP, n = 210; CHOP, n = 208), any-grade treatment emergent adverse events (TEAEs) that occurred ≥ 40% in the Ro-CHOP or CHOP arms, respectively, included anemia (67% vs 38%), nausea (55% vs 31%), thrombocytopenia (52% vs 17%), neutropenia (51% vs 37%), and vomiting (40% vs 10%). Grade 3/4 TEAEs that occurred in ≥ 30% of patients in the Ro-CHOP or CHOP arm, respectively, included thrombocytopenia (50% vs 10%), neutropenia (49% vs 33%), anemia (47% vs 17%), and leukopenia (32% vs 20%). One grade 5 TEAE occurred in the Ro-CHOP arm (E. coli sepsis), and 2 occurred in the CHOP arm (colitis and acute cholecystitis). In the Ro-CHOP vs CHOP arms, TEAEs led to CHOP dose interruption in 75 (36%) vs 42 (20%) patients, reduction in 54 (26%) vs 31 (15%) patients, and discontinuation in 7 (3%) and 6 (3%) patients, respectively. In the Ro-CHOP arm, TEAEs led to romidepsin interruption, reduction, and discontinuation in 132 (63%), 77 (37%), and 17 (8%) patients, respectively. Conclusions: The addition of romidepsin to CHOP did not improve PFS, the primary endpoint of the study, and response rates and OS appeared similar with the combination. The toxicity profile of Ro-CHOP was consistent with its phase Ib/II data, with no unexpected findings. The high rates of TEAEs with the addition of romidepsin hampered the ability to adequately administer 6 cycles of CHOP. Additional exploratory analyses to compare Ro-CHOP outcomes in specific patient subgroups are ongoing. The combination of CHOP plus romidepsin does not represent an advance in the standard of care for patients with previously untreated PTCL. Figure Disclosures Bachy: Beigene: Membership on an entity's Board of Directors or advisory committees; Roche, Gilead: Consultancy; Amgen: Research Funding; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria. Camus:PFIZER: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); JANSSEN: Honoraria; AMGEN: Honoraria. Thieblemont: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); 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; Incyte: 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; 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); 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); 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); Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Bayer: Honoraria. Casasnovas:Amgen: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy, Honoraria. Ysebaert:Roche: Consultancy; AbbVie: Consultancy; Janssen: Consultancy. Guidez:BMS: Honoraria; CELGENE: Honoraria; TAKEDA: Honoraria; JANSEN: Honoraria; AMGEN: Honoraria; Service Hématologie et Thérapie cellulaire CHU POITIERS: Current Employment. Kim:JJ: Research Funding; Celltrion: Research Funding; Kyowa Kirn: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; Pfizer: Research Funding; F. Hoffmann-La Roche: Research Funding. Lim:National Cancer Centre Singapore: Current Employment. André:Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Johnson & Johnson: Research Funding; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Novartis: Consultancy, Research Funding; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy; Celgene: Other, Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy; Seattle Genetics: Consultancy. Martin Garcia-Sancho:Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy; Roche, Celgene, Janssen, Servier, Gilead: Honoraria. Penarrubia Ponce:Novartis: Consultancy; Takeda: Consultancy, Honoraria; Janssen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Servier: Honoraria; HOSPITAL CLINICO UNIVERSITARIO DE VALLADOLID: Current Employment; Abbvie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy; Celgene: Consultancy, Honoraria; Incyte: Consultancy. Staber:msd: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Celgene/ BMS: Consultancy, Honoraria. Trotman:BeiGene: Research Funding; Takeda: Research Funding; F. Hoffmann-La Roche: Research Funding; Celgene: Research Funding; PCYC: Research Funding. Hüttmann: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); Roche: Other: Travel expenses; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Seattle Genetics: Research Funding; Lead Discovery Center GmbH: Consultancy; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria. Gaulard:Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); INNATE PHARMA: Research Funding; TAKEDA: Consultancy, Honoraria, Research Funding; CHU Henri Mondor, Assistance Publique-Hôpitaux de Paris: Current Employment. Delfau-Larue:MUNDIPHARMA: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); ROCHE: Honoraria; GILEAD: Honoraria; AMGEN: Honoraria. De Leval:Lausanne University Hospital & Lausanne University Institute of Pathology: Current Employment; Lunaphore Technologies SA: Consultancy, Honoraria; Abbvie: Honoraria; Roche Diagnostics: Honoraria. Meignan:ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Li:BMS: Current Employment, Current equity holder in publicly-traded company. Morschhauser:F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Servier: Consultancy. Delarue:Celgene International, a BMS company: Current Employment; BMS: Current equity holder in private company. OffLabel Disclosure: Romidepsin is not approved for patients with previously untreated PTCL.