T-cell non-Hodgkin Lymphoma Research Articles

Outcomes of contemporary novel agent incorporation in relapsed/refractory PTCL

Background: Conventional salvage chemotherapy has limited efficacy in relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). In the last decade, several novel agents have been approved; however, their impact on real world survival remains to be defined. In this multi-center retrospective analysis, we assessed survival following initial progression with respect to novel agent exposure in patients who did not receive stem cell transplant (SCT). Methods: Patients with PTCL from 1998 to 2021 at Columbia and Cornell were included after IRB approval. Medical records were reviewed for baseline characteristics, treatment including (1) novel agents, (2) chemotherapy, and (3) auto- and/or allo-SCT across all lines of therapy. Event-free survival (EFS) was calculated as time from 1st progression to 2nd progression, re-treatment, or death. Subsequent OS (sOS) was calculated from date of first progression to death or last follow-up. Kaplan-Meier method was used to estimate survival probability. Survival difference was tested by log-rank and Cox regression analysis. Results: A total of 348 patients with PTCL were identified, of which 189 had R/R disease and 156 had sufficient data for analysis. The median follow-up was 45.4 m from 1st progression. Baseline characteristics are shown in Figure 1A. The major PTCL subtypes were AITL (N = 52, 27%), PTCL-NOS (N = 41, 21.7%), ATLL (N = 33, 17.5%), and ALCL (N = 23, 12.2%). Median age at diagnosis was 58. Following initial progression, 21 (11.1%) received auto-SCT, and 42 (22.2%) received allo-SCT in second or later lines. Out of those patients who did not undergo SCT (n = 93), 66 (70.9%) received novel-agent-containing regimen only and 27 (29%) received chemo-only in second and later lines. Median sOS from date of initial progression for the entire cohort was 21.3 m. In patients who did not receive SCT, sOS for chemo-only versus novel-agent-containing regimen only was 4.9 m versus 13.0 m, respectively (p = 0.132) with hazard ratio 0.66 (95% CI: 0.39–1.14, p = 0.1349), illustrated in Figure 1B. EFS from first progression in novel-agent-containing regimen only was 4.2 m versus chemo-only 3.6 m (p = 0.6131) with hazard ratio 0.88 (95% CI: 0.54–1.44, p = 0.6137). Keywords: Aggressive T-cell non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. M. R. Seshadri Consultant or advisory role: Consulting for Gilead and Beigene Research funding: Research support from Roche and Eli Lilly

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: TFH lymphomas (TFHL) commonly harbor mutations in TET2, RHOA, DNMT3A and IDH2. While RHOA and IDH2 appear restricted to the neoplastic cells, TET2 and DNMT3A mutations occur in a significant proportion of cases in a hematopoietic progenitor cell and can also be detected in B or myeloid cells. Cell-free DNA (cfDNA) sequencing allows the detection of circulating tumor DNA in solid cancers or B-cell lymphomas, with predictive value, but few data exist on cfDNA sequencing in TFHL. Methods: In the frame of the ORACLE study, a phase 3 trial comparing oral azacitidine to investigator choice treatment in relapsed or refractory TFHL patients, we collected tumor biopsies and plasma in streck tube at inclusion, after 3 cycles, and at progression. Tumour and cfDNA were sequenced by NGS using 9 genes, amplicon-based libraries. Median sequencing depth was 2386X in tumor and 3519X in cfDNA. Results: Among patients with confirmed TFHL treated in LYSA centers, we collected 45 samples at inclusion, 16 after cycle 3, and 14 at progression. The median cfDNA concentration at each time point was respectively 7507 (IQR 3418–19414), 5182 (3438–12429), and 15750 (7316–26953) hEG/mL. Results of cfDNA at inclusion and tumor sequencing were compared in 43 patients. Common TET2 mutations were detected in the tumor of 36/43 (84%) and in cfDNA of 33/43 (77%) patients, with a median variant allele frequency (VAF) of 17.75% vs. 9.8% respectively. RHOAG17V was detected in 29/43 (67%, VAF 10%) and in 24/43 (59%, VAF 4.4%), DNMT3A in 13/43 (30%, VAF 17.9%) and 15/73 (35%, VAF 17.9%), and IDH2 in 12/43 (28%, VAF 5.9%) and 8/43 (19%, VAF 5.4%) of tumor biopsies and cfDNA samples respectively. Only one patient had detectable TET2, DNMT3A, IDH2, and RHOA mutations in the cfDNA and not in the tumor biopsy, corresponding to a tumor with low neoplastic cell content. By contrast, 3 patients had DNMT3A mutations, not affecting the R882 residue, detected in the cfDNA but not in the tumor likely corresponding to clonal hematopoiesis not related to the TFHL. We also compared 25 paired cfDNA samples collected at inclusion and after cycle 3 (including progression sample if occurring at cycle 3 or before). In all but one patient, we observed the persistence of TET2 and DNMT3A mutations, even in responding patients, confirming that these mutations are not restricted to neoplastic cells, and suggesting that treatment, especially with 5-azacitidine, does not affect the clonal hematopoiesis. By contrast, among the 14/25 patients with a detectable RHOA mutation in cfDNA at inclusion, progression-free survival was longer in the 4 patients with the disappearance of the RHOA mutations in cfDNA at cycle 3 than in the 10 others (median 29 vs. 3 months, p = 0.01). The research was funded by: BMS Force Hémato Keywords: Aggressive T-cell non-Hodgkin lymphoma, Liquid biopsy, Minimal residual disease No conflicts of interests pertinent to the abstract.

The mTOR kinase inhibitor everolimus synergistically enhances the anti‐tumor effect of the Janus kinase 1 (JAK1) inhibitor AZD4205 on Peripheral T cell lymphoma

Introduction: Peripheral T-cell lymphoma (PTCL) constitute a heterogenous group of non-Hodgkin lymphomas, which is distinguished by their aggressive courses and poor clinical outcomes. Multiple researches have indicated that the JAK/STAT pathway acts as an important role in the mechanism of TCL pathogenesis. Preliminary results from related clinical studies showed that JAK inhibitors have a high remission rate and durable response in PTCL patients. AZD4205 is a potent JAK1-selective inhibitor currently evaluated in phase II clinical studies in PTCLs, which could reduce the side effects caused by JAK2 blockade by selectively targeting JAK1. Therefore, the aim of this study is to explore the efficacy and appropriate combination regimen of the novel JAK1 inhibitor AZD4205 in PTCL and to decipher the underlying anti-tumor mechanism. Methods: We analyzed the expression of JAK/STAT pathway in PTCL tissues via bioinformatics analysis and IHC. In vitro cell viability was assessed by using Cell Titer-Glo Luminescent assay. Induction of cell apoptosis was measured by flow cytometry. Western blot was utilized to identify the influence of AZD4205 on the intracellular relevant signaling pathways. The effects of AZD4205 on the transcriptome of PTCL cells were analyzed via transcriptome sequencing technology. High-throughput compounds screening was applied to explore potential combination therapeutic targets of AZD4205. Tumor-bearing mouse models were established to validate the efficacy and safety of AZD4205 and the combination regimen. Results: High expression of phosphorylated JAK1 in PTCL tissues are potential poor prognostic factors. The JAK1 inhibitor AZD4205 inhibited the proliferation of PTCL cells and down-regulated the activation of JAK/STAT signaling pathway. In addition, AZD4205 induced apoptosis in PTCL cells, and showed anti-tumor effects in vivo. However, AZD4205 also induced adverse effects of hepatic impairment and dyslipidemia in vivo. Transcriptome sequencing analysis revealed that AZD4205 treatment upregulated the expression of mTOR pathway-related genes. Moreover, high-throughput screening assay showed that the mTOR inhibitor everolimus significantly enhanced the inhibitory efficacy of AZD4205. We further confirmed that AZD4205 combined with the mTOR inhibitor everolimus exerted synergistic anti-PTCL efficacy both in vitro and in vivo, and the combination regimen significantly reduced AZD4205-induced adverse effects. The RNA-seq results suggested that the combination treatment affected the cholesterol homeostasis pathway and a further validation of the combined anti-PTCL effect of mevastatin and AZD4205 was confirmed in mouse models. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Combination Therapies, Molecular Targeted Therapies No conflicts of interests pertinent to the abstract.

A MULTI‐CENTER RETROSPECTIVE STUDY OF PEMBROLIZUMAB IN PATIENTS WITH RELAPSED OR REFRACTORY EXTRANODAL NK/T‐CELL LYMPHOMA

Background: Extranodal natural killer T-cell lymphoma (ENKTL) is an aggressive malignancy with a dismal prognosis. PD-1 blockade with pembrolizumab has shown promising activity in relapsed/refractory (R/R) ENKTL in case series. Real-world data about the efficacy of pembrolizumab in R/R ENKTL patients are limited. Methods: We performed a multicenter retrospective study to evaluate pembrolizumab efficacy and safety in patients with R/R ENKTL from 10 academic centers in South Korea. Pembrolizumab 100 mg was administered intravenously every 3 weeks. Results: A total of 24 patients were enrolled. The median age was 67 years old (range, 36–87) and 29.2% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater. Pembrolizumab was administered as 2nd-, 3rd- and 4th or greater line chemotherapy in 9 (37.5%), 9 (37.5%), and 6 (25.0%) patients, respectively, and median 3 cycles (range 1–21) of pembrolizumab were given. In response evaluation, complete remission (CR) and partial response (PR) was achieved in 6 (25.0%) and 3 (12.5%), respectively. The median progression-free survival and overall survival were 2.0 months (95% CI, 0.9–3.0) and 8.0 months (95% CI, 0.0–22.4), respectively. Multivariate analysis indicated that ECOG PS was the only significant predictor of PFS after pembrolizumab treatment (hazard ratio, 5.33; 95% confidence interval, 1.09–26.1; P = .039) Overall, 14 (58.3%) patients experienced adverse events (AEs), with fatigue (n = 7, 29.1%) being the most common Eight patients (33.3%) developed G3-4 AEs, the most frequent of which was neutropenia (4,16.7%) Conclusion: Pembrolizumab could be a therapeutic approach for the control of R/R ENKTL. Keyword: Aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Peripheral T cell lymphoma (PTCL) is a group of highly heterogeneous malignancies with a high rate of disease relapse or progression.Tucidinostat (formerly known as chidamide(C)),a novel histone deacetylase inhibitor, has shown promising results in T-cell lymphomas by multiple mechanisms and is currently approved by the Chinese FDA for relapsed/refractory PTCL.In this retrospective study,we compared the efficacy of Tucidinostat with CHOP-like (C+CHT) and CHOP-like (CHT) alone in newly diagnosed PTCL. Methods: We reviewed 132 patients with PTCL diagnosed at the Shanxi Provincial Cancer Hospital Hematology Oncology Center from January 2015 to July 2021,of whom 109 patients were diagnosed with newly diagnosed PTCL,with last follow-up as of November 2022.Those in the C+CHT group who achieved complete remission received Tucidinostat maintenance therapy.The two groups of patients were subjected to 1:1 propensity score matching, according to whether the Prognostic index for PTCL-NOS(PIT) ≥2, pathological subtype, age＞60 years, and gender (matching tolerance = 0.024),36 pairs (n = 72) were matched. The primary study endpoint of this study was progression-free survival (PFS), and the secondary study endpoints were overall survival (OS), objective remission rate (ORR) at the end of the first-line chemotherapy regimen, CR rate and adverse events (AEs). Results: After matching,no statistical difference was found in baseline characteristics between C+CHT (n = 36) and control (n = 36) groups (all P > 0.05).The ORR for C+CHT group and control group were 72.2% and 52.8% (p = 0.088), with the CR rate of 44.4% and 33.3% (p = 0.334). After median follow-up of 18.7 (range 1.0–82.8) months, the median PFS in C+CHT group and control group were 17.2 and 5.0 months, respectively; the 2-year PFS was 67.9% and 25.3%, respectively; the median OS was 43.7 and 18.5 months, respectively; and the 2-year survival rate was 65.6% and 35.7%, respectively. Compared with control group, C+CHT group displayed significantly longer PFS(HR = 0.553, 95% CI: 0.319–0.959,p = 0.035, Figure 1A) and OS(HR = 0.483, 95% CI: 0.251–0.930, p = 0.029, Figure 1B). Cox analyses further verify that the effect values were basically consistent with the matching results (PFS HR = 0.552, OS HR = 0.469). Common grade 3–4 hematological AEs in the C+CHT group were leukopenia (55.9%), neutropenia (52.9%), thrombocytopenia (26.5%), and anemia (20.6%), the incidence of AEs was comparable to that of the control group. Common non-hematological AEs, the incidences of elevated AST and ALT were higher in the C+CHT group than in the control group(p = 0.028 and p = 0.021, respectively), but they were mainly grade 1 AEs, which could be resolved with supportive treatment. Keyword: aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

KILT: A RANDOMIZED NON‐COMPARATIVE PHASE II LYSA STUDY OF LACUTAMAB WITH GEMOX VERSUS GEMOX IN RELAPSED/REFRACTORY PERIPHERAL T‐CELL LYMPHOMA

Background: Peripheral T-cell Lymphoma (PTCL) is a heterogeneous group of mature T-cell lymphomas (TCL) with adverse outcomes. Current treatment options for relapsing PTCL are limited. KIR3DL2 is a killer immunoglobulin-like receptor that is expressed across different subtypes of TCL, including approximately 40% of PTCL. Lacutamab is a humanized first-in-class monoclonal antibody designed to deplete KIR3DL2-expressing cells via ADCC and phagocytosis. In a previous phase I trial in relapsed/refractory cutaneous TCL, lacutamab showed adequate safety profile with no dose limiting toxicities and a global response rate of 43%. TELLOMAK multi-cohort phase II trial (NCT03902184) in advanced TCL is ongoing. Lacutamab has not been previously investigated as a combination therapy. Preclinical studies have shown that lacutamab selectively killed KIR3DL2-positive primary cells ex vivo from patients with PTCL. A combination of lacutamab with gemcitabine and oxaliplatin (GemOx) enhances NK cell anti-tumor activity in vitro. Methods: This is an open label, multi-center, international, randomized non-comparative phase II trial to compare the safety and efficacy of lacutamab in combination with GemOx vs. GemOx alone in patients with any subtypes of relapsed/refractory KIR3DL2-positive PTCL. The design is non comparative meaning that the control arm will ensure that the assumptions used for sample size calculation are verified. For that reason, randomization is unbalanced in favor of the experimental arm (2:1). Patients are stratified according to R/R status and should have received ≤2 prior systemic therapies. In the experimental arm, patients are treated for 6 cycles of lacutamab 750 mg (intravenous infusion) + GemOx every 3 weeks as induction, and with lacutamab every 4 weeks as maintenance for up to a maximum of 2 years if they reached at least a partial response after induction. All patients should have a KIR3DL2 expression ≥1% as assessed centrally by immunohistochemistry. The primary endpoint is the median modified progression-free survival using the Lugano 2014 criteria. Secondary endpoints include safety, other efficacy endpoints and exploratory biomarker analyses. 56 patients are planned to be enrolled in France, Belgium, Spain and Germany. The trial is currently enrolling in 37 medical centers in France and Belgium. The sponsor of the trial is the Lymphoma Academic Research Organisation (LYSARC) in collaboration with Innate Pharma. Trial registration: NCT04984837. The research was funded by: The research was funded by Innate Pharma Keywords: aggressive T-cell non-Hodgkin lymphoma, immunotherapy, ongoing trials Conflicts of interests pertinent to the abstract. M. Cheminant Research funding: Innate Pharma J. Bruneau Research funding: Innate Pharma C. Herbaux Honoraria: AbbVie, Janssen, Roche, Gilead Research funding: AbbVie A. Wolfromm Consultant or advisory role Takeda O. Tournilhac Honoraria: Amgen, Janssen, Gilead, Abbvie, BluePrint, Roche Educational grants: Amgen, Janssen, Gilead, Abbvie, BluePrint, Roche P. Gaulard Research funding: Innate Pharma N. Ortonne Research funding: Innate Pharma O. Hermine Research funding: Innate Pharma

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Peripheral T cell lymphomas (PTCLs) are a rare, heterogeneous group of hematological malignancies with too often poor prognosis for almost all subtypes. The T-Cell Project (TCP; registered at clinicaltrials.gov identifier: 01142674) was a prospective cohort study aimed at better understanding clinical characteristics and outcome of patients with PTCL. Here we report the results of 10-year follow up, focused on late relapses and long term survival. Methods: The TCP started in September 2006 as a prospective registry of patients with mature PTCLs. Between December 2006 and March 2018, 1669 patients were registered and 1,553 patients were eligible in the study. Recently, a survey was launched asking for the willingness of the centers to provide long term follow up data. So far, out of 1,553 eligible patients, 713 were referred by Centers that provided information on long-term follow-up and have been included in the present analysis; 840 cases, referred by centers that did not participate to this long term survival analysis were excluded. However, both groups showed similar baseline characteristics and 5y OS (44% vs. 44%) and PFS (37% vs. 35%), thus minimizing selection biases Result: Out of these 713 patients, 255 patients (36%) had a diagnosis of PTCL NOS, 133 (19%) of AITL, 124 (17%) of ALCL ALK-, 62 (8%) of ACL ALK- and 13 (2%) of NKTCL. The median age at diagnosis was 56 years (range, 18–88 years), with a slight male predominance (55%). B symptoms were present in 44% and extranodal involvement in 56% of patients. Patients receiving chemotherapy alone and radiotherapy alone comprises 58% and 3% respectively; while the 18% received CHT+RT. Of evaluable patients, 60% received anthracycline-based chemotherapy, 24% anthracycline/etoposide and 12% etoposide alone. A minority (16%) of the total cohort underwent high-dose chemotherapy with autologous stem cell support as first-line consolidation. After a median follow-up of 82 months, 35 (12%) of patients had an event of progression or death beyond 5 years. The 5- and 10-year rates of both overall survival and progression-free have decreased from 44% and 40%, to 31% and 27%, respectively (Figure 1). For those patients alive at 5 years, the chance of surviving the subsequent 5 years was 83% (95% CI: 61–99). Furthermore, for patients progression free at 5 years the probability of being disease alive and free in the subsequent 5 years was 78% (95% CI: 60–96). Ten year OS and PFS rates for patients alive at 5 years were: 77% and 73% for PTCL NOS, 85% and 76% for AITL, 88% and 87% for ALCL ALK-, 100% and 100% for ALCL ALK+), and 78% and 80% (for NKTCL). Keyword: aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

HOW WE ARE SUCCESSFUL IN THERAPY OF T‐CELL LYMPHOMA PATIENTS (≥70 YEARS). REAL‐WORDL ANALYSIS FROM THE CZECH LYMPHOMA STUDY GROUP REGISTRY (NIHIL).

Background: T-cell lymphomas (TCL) belong to the malignancies with poor prognosis. Up to now, the core of treatment is based on chemotherapy. The best results are reached with intensive regimen (etoposide-based; CHOEP) and autologous stem cell transplantation (autoTx). In the patients ≥70 years is not usually possible to apply this strategy. Methods: In total 1 432 patients (pts) with newly diagnosed T-cell lymphomas (1999–2020) was enrolled in NIHIL database (Clinical Trial gov. NCT03199066), 503 patients with a diagnosis other than PTCL, AITL and ALCL, and 23 patients with no follow-up information were excluded. We selected 240 patients ≥70 years at lymphoma diagnosis with the ALCL, PTCL-NOS and AITL/TFH-TCL (around 67% patients). Results: In the cohort of 240 patients ≥70 years, PTCL-NOS (131/240; 54.6%) was the most frequent, followed by ALCL (61/240; 25.4%) and AITL (48/240; 20%). Median age was 75 yrs (range; 70-95), 131/240 (54.6%) were men, ECOG >2 had 45/240 (19.3%) pts, advanced disease (stage III or IV) was in 180/240 (76.2%) pts, and 161/240 (68.8%) pts had LDH above normal range. First-line therapy received 233/240 (97.1%) patients, systemic chemotherapy was administered in 201/240 (83.8%), the most frequent regimen was CHOP in 114/201 (56.7%), COP in 15%, etoposide-based regimens were administered in 6.5% patients only; no patients received alloTx or autoTx, monoclonal antibody (brentuximab vedotin, alemtuzumab, rituximab) was given in 11/201 (5.5%) cases. Best response after first-line treatment included 83 (34.6%) CR/Cru, 32 (13.3%) PR, 10 (4.2%) SD and 37 (15.4%) PD, but there were 58 (24.2%) pts with not evaluable and 20 (8.3%) pts with unknown response. Median OS (95% CI) was 1.2 yrs (0.9–1.5), and median PFS 0.8 yrs (0.7–1.0). From the subgroup of 78 patients with unknown/unevaluable response, 94.6% died with median 0.32 yrs (range; 0.14-5.6). Conclusion: TCL of elderly ≥70yrs represents difficult subgroup of patients with increasing proportion of prognostically worse subtypes (PTCL-NOS, AITL). Despite chemotherapy is administered in majority of cases, the response is reached in half of them only, but around another third of patients died early during or immediately after therapy. Keyword: Aggressive T-cell non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract D. Belada Consultant or advisory role Gilead, Roche, Novartis, Takeda Educational grants: Roche, Gilead Sciences H. Mocikova Consultant or advisory role Takeda, Roche, Astra Seneca, Janssen, Abbvie Educational grants: Janssen, Takeda J. Duras Consultant or advisory role Roche, Takeda, Celgene

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Relapsed/refractory (r/r) peripheral T cell lymphomas (PTCL) are highly aggressive tumors associated with very poor prognosis. We recently described a new targeting strategy based on the mutually exclusive expression of T cell receptor beta-chain constant domains 1 and 2 (TRBC1 and TRBC2) (Maciocia, PM. et al. Nat Med, 2017) which can spare a proportion of the normal T cell compartment. Here we describe first in human clinical findings of AUTO4, a TRBC1 directed autologous CAR T cell therapy for patients with TRBC1-positive PTCL. Methods: NCT03590574 is an ongoing, multi-centre, single-arm phase 1/2 study of AUTO4 in r/r TRBC1-positive PTCL. Here we report the findings of the dose escalation. Four dose levels were explored: 25 × 106, 75 × 106, 225 × 106, and 450 × 106 CAR T cells were administered as a single dose. CAR T-cell products were generated using a semi-automated closed process. The initial AUTO4 manufacturing process A was optimized and is now being used in process B to define the recommended phase 2 dose. Primary endpoints in phase 1 are incidence of ≥Grade 3 toxicity occurring within 60 days of AUTO4 infusion and the frequency of dose limiting toxicities (DLT) within 28 days of AUTO4 infusion. Overall response (CR + PR) rate by Lugano PET-CT criteria is a secondary endpoint. Results: As of 8 February 2023, 12 patients (10 process A, 2 process B) have been treated with AUTO4. The median age was 57 years (range 34–72) with a median prior lines of 2 (range 1–5). 7 patients were diagnosed with PTCL-NOS, 4 with AITL (Angioimmunoblastic T-cell lymphoma) and 1 with ALCL (Anaplastic large cell lymphoma). Chemotherapy bridging was given to 70% of patients and 4/8 CD30+ patients recieved brentuximab as bridging or as prior line therapy. 3/12 patients had prior autoSCT. The most common treatment adverse events were transient Grade1–4 neutropenia, thrombocytopenia. Lymphopenia was observed with CD3+ lymphocytes recovering to baseline levels after pre-conditioning. No ≥Grade 3 infections were observed. Any grade CRS was observed in 6/12 patients (5 at 450 × 106, 1 at 250 × 106) and one patient developed Grade 3 CRS which resolved within 3 days. No ICANS or DLTs were observed. Response at month 1 was evaluable in 9/10 patients using process A. Five patients were in complete metabolic response (CMR) (1/5 was in CMR at the time of lymphodepletion), 1 patient achieved a partial response (PR) and 3 patients had no response. At the 450x106 dose level, 3/4 patients achieved CMR at month 1, and 2 of them are in ongoing remission at 12 and 15 months, respectively. The efficacy non-evaluable patient at month 1, due to COVID19 infection, showed no response at month 3 but achieved a delayed PR by month 9 without any further treatment. Conclusions: AUTO4 was well tolerated with no DLT. Ongoing CMR at months 12 and 15 are encouraging. Updated data and longer follow up using the improved manufacturing process B will be presented. The research was funded by: Autolus Ltd Keywords: aggressive T-cell non-Hodgkin lymphoma, cellular therapies, ongoing trials Conflicts of interests pertinent to the abstract J. Shang Employment or leadership position: Autolus Therapeutics E. Xue Employment or leadership position: Autolus Therapeutics M. Zhang Employment or leadership position: Autolus Therapeutics S. Basilico Employment or leadership position: Autolus Therapeutics M. Raymond Employment or leadership position: Autolus Therapeutics P. Lao-Sirieix Employment or leadership position: Autolus Therapeutics K. Lilova Employment or leadership position: Autolus Therapeutics W. Brugger Employment or leadership position: Autolus Therapeutics M. Pule Employment or leadership position: Autolus Therapeutics

A REAL‐WORLD STUDY OF CHIDAMIDE FOR PATIENTS WITH PERIPHERAL T‐CELL LYMPHOMA IN CHINA

Background: Peripheral T-cell lymphoma (PTCL) is featured with a poor survival outcome. Targeting histone deacetylases (HDACs) has become a novel treatment option for PTCL. Chidamide is the first oral selective HDAC inhibitor. Objective: This observational study aimed to investigate the efficacy and safety of Chidamide in patients with PTCL. Methods: From June 2015 to April 2022, 49 PTCL patients treated with Chidamide were included in this study. Objective responses, progression-free survival (PFS), overall survival (OS), and safety were analyzed. Results: The median age was 59 years (range, 30–85 years). Angioimmunoblastic T-cell lymphoma (AITL, 57.1%) was the main pathological subtype, followed by PTCL-not otherwise specified (PTCL-NOS, 14.3%), NK/T-cell lymphoma (NKTCL, 8.2%), anaplastic large cell lymphoma (ALCL, 6.1%) and other subtypes (14.3%). 77.6% of patients were previously untreated. 91.8% of patients had stage Ⅲ/Ⅳ disease. Thirty-three patients achieved objective responses with an overall response rate (ORR) of 67.4%, including 21 patients with complete response (CR). The 2-year PFS rate and 2-year OS rate were 51.5% and 68.5%, respectively. Among the 27 previously untreated patients who received Chidamide combined with chemotherapy, the ORR of all various PTCL subtypes, AITL and PTCL-NOS were 85.2%, 68.8% and 75.0%, respectively. The most common adverse events (AEs) were hematological toxicities. 24.5% of patients reduced the dosage or stopped using Chidamide due to AEs. No treatment-related death occurred. Conclusion: The favorable efficacy and safety profiles indicate that Chidamide would be a new therapeutic option in patients with PTCL. Encore Abstract - previously submitted to EHA 2023 Keyword: Aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Enteropathy associated T-cell lymphoma (EATL) is a rare peripheral T-cell lymphoma (PTCL) associated with celiac disease that has a poor prognosis. Treatment of EATL is challenging due to the lack of clinical trials. In PTCL, the preferred chemotherapeutic regimen is cyclophosphamide, doxorubicine, vincristine and prednisone (CHOP), either with or without etoposide (CHOEP) followed by consolidative autologous stem cell transplantation (ASCT). This nationwide Dutch study describes the incidence, treatment and outcome of all reported EATL cases. Methods: All patients diagnosed with EATL between 1989 and 2020 were identified in the Netherlands Cancer Registry with survival follow-up through February 1, 2022, thereby excluding post-mortem diagnoses. Baseline characteristics, treatment modality and survival outcomes were collected. Patients were categorized into three periods (1989–1999, 2000–2010, 2011–2020) and in limited (I/II) or advanced (III/IV) stage disease. For patients diagnosed as of 2014, detailed information on treatment regimens was available. Overall survival (OS) was defined as the time from diagnosis to all-cause-death. Multivariable analysis of OS was performed using Cox regression. Results: We included 338 patients (median age 67 years [range 37–90 years], 57% male) in our study. Limited stage disease was more common than advanced stage (51% versus 38%, 11% undetermined). Treatment consisted of surgery (18%), chemotherapy (CT; 33%), CT followed by ASCT (3%), surgery and CT (19%), surgery and CT followed by ASCT (3%), surgery and RT (1%) or no treatment (23%). Between 2014 and 2020, the most commonly used CT regimens were CHOP (54% in limited stage and 66% in advanced stage disease) and CHOEP (32% in all stages). Over time, the use of CT increased from 22% to 46%, whereas resection only and resection combined with CT became uncommon (decrease from 33% to 7%, and 23% to 5% respectively; Figure 1). Two-year OS improved from 19% in 1989–1999 to 26% in 2011–2020. The 6-month, 2-year and 5-year OS for limited stage were 51%, 24% and 15% (median OS 6.3 months) and for advanced stage 44%, 16% and 7% (median OS 5.1 months), respectively (Figure 2). In multivariable analysis, surgery only (hazard ratio [HR] 1.97; 95% confidence interval [CI] 1.41–2.74), no therapy (HR 3.66; 95% CI: 1.72–3.76) and advanced stage disease (HR 1.31; 95% CI: 1.02–1.70) were independent predictors of poor prognosis, whereas ASCT (HR 0.38; 95% CI: 0.17–0.81) was associated with improved OS. Keyword: aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

ENHANCER OF ZESTE HOMOLOG 2 (EZH2) INHIBITOR SHR2554 IN RELAPSED OR REFRACTORY (R/R) PERIPHERAL T‐CELL LYMPHOMA (PTCL): UPDATED OUTCOMES FROM THE FIRST‐IN‐HUMAN PHASE 1 STUDY

Introduction: Inhibition of histone methyltransferase EZH2 represents a rational therapeutic strategy for lymphomas. SHR2554 is an oral small-molecule inhibitor exhibiting potent selectivity for EZH2. The multicenter, 2-part, phase 1 study was initiated to assess SHR2554 in patients (pts) with r/r lymphomas (NCT03603951). In part I, 350 mg BID was established as the recommended phase 2 dose (RP2D) based on the findings in the dose-escalation and expansion phases; subsequently, pts with selected lymphoma subtypes were recruited in the clinical expansion phase to receive SHR2554 at RP2D (Y Song et al. Lancet Haematol, 2022). Here we report the updated results of part I focusing on PTCL pts at RP2D. The prognosis of PTCL is extremely poor due to low response to chemotherapy regimens and limited treatment options thereafter, highlighting an urgent, unmet medical need. Methods: Pts with histologically confirmed PTCL that had relapsed or were refractory to ≥1 line of prior systemic therapy were eligible for inclusion in part I of this study. Efficacy and safety were assessed in PTCL pts who received at least one dose of SHR2554 at 350 mg BID. Results: Totally, 28 pts were included in this analysis: median age, 56 y (range 30–70); ECOG PS 1, 64.3% (18/28); median lines of prior systemic therapies, 2 (range 1–14). At data cutoff on 31 August 2022, the median follow-up duration was 11.9 mo (range 0.9–23.9). 17 pts achieved complete or partial response, resulting in a confirmed objective response rate (ORR) of 60.7% (95% CI 40.6–78.5). Responses were still ongoing in 58.8% (10/17) of the responders; estimated median duration of response (DoR) was 12.3 mo (95% CI 7.4–NR). 16 (57.1%) pts had disease progression or died; median progression-free survival (PFS) was 11.1 mo (95% CI 5.3–22.0). 4 (14.3%) deaths occurred; 1-y overall survival rate was 92.2% (95% CI 72.1–98.0). Of the 28 pts, 17 were diagnosed with angioimmunoblastic T-cell lymphoma (AITL), and 11 had PTCL not otherwise specified (PTCL-NOS). AITL pts showed better outcomes than PTCL-NOS pts: ORR, 76.5% versus 36.4%; median DoR, 20.3 versus 3.3 mo; median PFS, 22.1 versus 5.0 mo (Table). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 14 of the 28 pts (50.0%), with the most common being decreased platelet count (32.1%), decreased white blood cell count (14.3%), decreased neutrophil count (14.3%), and anemia (14.3%). One (3.6%) pt discontinued treatment due to TRAE (interstitial lung disease). No treatment-related deaths were reported. Conclusions: This extended follow-up analysis further provides evidence of potent anti-tumor activity, durable response, and acceptable safety of SHR2554 in pts with r/r PTCL. The research was funded by: The study was sponsored by Jiangsu Hengrui Pharmaceuticals Co., Ltd. Keywords: aggressive T-cell non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract Y. Shen Employment or leadership position: Jiangsu Hengrui Pharmaceuticals J. Shen Employment or leadership position: Jiangsu Hengrui Pharmaceuticals Z. Xiao Employment or leadership position: Jiangsu Hengrui Pharmaceuticals

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: The primary analysis of the Ro-CHOP trial (NCT01796002) demonstrated that romidepsine (Ro) plus CHOP did not provide an increased efficacy compared with CHOP alone in patients with previously untreated peripheral T-cell lymphoma (PTCL). We report here the final analysis of the Ro-CHOP trial. Methods: The study was an open-label multicenter randomized (1:1) phase III study of Ro-CHOP versus CHOP as frontline treatment of patients 18–80 years with PTCL. The primary endpoint was progression-free survival (PFS) according to IWG 1999 criteria. Overall survival (OS) was a secondary endpoint, relapse patterns and PFS/OS after the first progression (PFS2/OS2) were analyzed post-hoc. The cut-off date was set to 2022/12/13, that is, five years after the last patient was enrolled. Results: 211 and 210 patients were assigned to receive 6 cycles of Ro-CHOP or CHOP in 3-week cycles, respectively. Median age was 65 (25–81) years. With a median follow-up of 71.8 months, 271 patients (64.4%) presented a PFS event by independent RAC assessment. Median PFS was 12 months (95% CI = [9; 25.8]) and 10.2 months ([7.4; 13.2]) for Ro-CHOP and CHOP, respectively (HR = 0.79 [0.62; 1.005], p = 0.054, 2-sided p-value). Based on 229 deaths, median OS was 62.2 months and 43.8 months for Ro-CHOP and CHOP, respectively. The causes of death were the following: lymphoma (n = 165, 72.4%), concurrent illness (n = 30, 13.2%), other reasons (n = 12, 5.3%), toxicity of salvage treatment (n = 8, 3.5%), toxicity of study treatment (n = 4, 1.8%), unknown (n = 9, 3.9%). No new safety signal was observed. A significantly prolonged PFS in the follicular helper T-cell (TFH) lymphoma subgroup (centrally reviewed) was still observed with this longer follow-up. The median PFS was 19.5 months ([11.5; 44.4]) in the Ro-CHOP arm and 10.6 months ([7.4; 14.9) the CHOP arm with a HR of 0.703 ([0.502; 0.985], p = 0.0395). Additional treatment was given to 251 patients after progression (Ro-CHOP = 115, and CHOP = 136), leading to an overall response rate of 35.7% (CR/CRu: 21.7%) and 31.6% (CR/CRu: 22.1%) in the Ro-CHOP and CHOP groups, respectively. Overall, 191 of the 251 patients (76.1%) progressed after second-line therapy, and 20 patients died without a second progression (8.0%). The median PFS2 and OS2 were 3.3 months (95% CI, [2.7; 4.5]) and 11.5 months ([9.6; 15.9]), respectively. Twenty-three patients (9.2%) received an allogeneic stem cell transplantation (median age 51 [29–70] years) and displayed 1-year PFS2 and OS2 rates estimated at 59.7% and 81.8%, respectively. Detailed outcome according to salvage treatment at progression will be presented at the meeting. The study was sponsored by the LYSARC, with funding provided by Celgene/BMS Keyword: aggressive T-cell non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract V. Camus Consultant or advisory role: Roche, BMS, Novartis, Kite-Gilead, Janssen, Abbvie, Sanofi, Octapharma, Kyowa Kirin Pharma Research funding: Iqone Healthcare, BMS Educational grants: Pfizer, Roche, BMS, Novartis, Kite-Gilead M. Delfau-Larue Honoraria: Takeda, Amgen, Roche, Gilead, Abbvie Research Funding: Celgene, BMS, Roche

Brigatinib in patients with ALK‐positive anaplastic large cell lymphoma who have failed brentuximab vedotin

ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) patients (pts) who have failed brentuximab vedotin (BV) have a poor prognosis with a median OS after BV failure of 2.9 months and 2-year OS of 27.1% (Chihara D, 2019). ALK-inhibitors have shown interesting results in relapsed ALK+ ALCL, but in these studies, most pts had not received prior BV, which does not correspond to current standards of treatment in adults. Furthermore, there are currently several ALK-inhibitors, but too few pts available to test them in this rare and difficult-to-treat population. It is therefore important to evaluate these ALK-inhibitors in preclinical studies, before selecting one for a clinical study. We carried out a preclinical study and then a real-life clinical study. We generated a patient-derived xenograft (PDX) model from a fresh lymph node biopsy of a 41-year-old man newly diagnosed with ALK+ ALCL. Our PDX closely mimicked the patient’s primary tumor, as assessed by pathology, FISH, TCR gene rearrangement, WES and RNA-seq. We used this model to assess 8 ALK-inhibitors (alectinib, brigatinib, ceritinib, crizotinib, ensartinib, entrectinib, lorlatinib, gilteritinib). We selected and recommended brigatinib for clinical off-label use based on our preclinical results and the safety profile in pts with ALK-positive non-small cell lung cancer (NSCLC). Between Jan 2020 and Oct 2022, 15 French adults who have failed BV started brigatinib. At brigatinib initiation, the median age was 35 y (19–73; 2 pts > 60 y), 8/15 were male, the median number of prior treatment lines was 2 (1–8), 4/15 (27%) had received prior crizotinib, including 3 crizotinib-resistant (crizo-R) and 1 crizotinib-sensitive (crizo-S) who relapsed after discontinuation of the drug. 4 pts had previously undergone stem cell transplantation (3 autoSCT, 1 alloSCT). ALCL was refractory to the last treatment in 10/15 pts. 10/11 pts had detectable ALK transcript in blood by RT-PCR. Pts received brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg), as recommended in ALK-positive NSCLC. The best ORR was 93% (14/15) with 73% (11/15) CR according to Lugano response criteria. 2 crizo-R and the crizo-S pts achieved CR, and 1 crizo-R pt reached PR. Time to achieve CR ranged from 8 to 325 days. 9 pts were monitored for ALK transcript in blood over time and kinetics correlated with response. 5 CR pts were bridged to alloSCT. There were 4 progressions/relapses after brigatinib initiation, all occurring within the first 6 months. After a median follow-up of 1.3 years, 1-year PFS and OS were 72% and 85%, respectively. There was no permanent discontinuation of brigatinib related to adverse event (AE), and 3 pts had dose reduction for moderate AE (1 dyspnea and 2 cramps), with complete resolution. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. D. Sibon Consultant or advisory role: Takeda, AbbVie, Janssen, Roche

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: The Nordic Lymphoma Group (NLG) performed a dose-finding/expansion trial evaluating pixantrone, etoposide, bendamustine and, in CD20+ lymphomas, rituximab (P[R]EBEN) in patients (pts) with relapsed diffuse large B-cell (DLBCL) or peripheral T-cell (PTCL) lymphomas. The regimen was out-patient based, and applicable in frail, heavily pre-treated pts. Here we present a long-term follow-up of the trial and a per-protocol correlative biological analysis of pre-therapeutic tumour biopsies looking for gene expression profiles associated with long-term response. Methods: We enrolled 60 pts (37 DLBCL and 23 PTCL; age range: 39–84 yrs, median: 71 yrs). Time to event parameters were analyzed by Kaplan-Meier estimates, log-rank test and Cox regression models. Pre-therapeutic biopsies from 42 pts (25 DLBCL, 17 PTCL) were analyzed for gene expression by NanoString PanCancer Pathways and Immune profiling panels (altogether 1348 genes). Results: Of the original 60 patients, 22 were alive at the time of the present analysis. The median follow-up of surviving pts was 41 mo (range 26–76 mo). The 38 deaths were due to: lymphoma (24; 63%), infections (3; 8%) and other causes (11; 29%: 1 lung carcinoma, 5 acute myeloid leukemia-AML, 1 myelodysplasia-MDS, 1 lung embolism, 1 allotransplant related and 2 unknown). Of the 6 pts with AML/MDS, 5 were PTCL and 1 DLBCL. Of 58 evaluable pts, 38 (65%) had a complete (CR) and 1 (3%) a partial response (B: 51%; T: 70%). The median duration of response (DoR) of the 38 CR pts was 17 mo (range 0.5–55 mo; B: 18 mo; T: 17 mo). Four pts were bridged to allogeneic transplant. The overall 5-yr OS and PFS were 33% and 19%, respectively. The median OS for DLBCL was 16.0 mo [IQR 7.0>] and for PTCL 18.0 mo [IQR 8.0>]. The median PFS for DLBCL was 10.0 mo [IQR 4.0–32.0] and for PTCL 10.0 mo [IQR 5.0–26.0]. To better understand molecular alterations underlying the delay of relapse in this heavily pre-treated elderly population, we determined differentially expressed genes between short (<12 mo) and long term (>12 mo) responders. In DLBCL, 31 genes showed significant differential expression between short- and long-term responders (P < 0.05). The latter had higher expression of genes related to transcription factor activity. The gene most significantly associated with long-term response was Neutrophil Cytosolic Factor 4 (NCF4). In PTCL, 23 genes were differentially expressed between short- and long-term responders, the latter showing enrichment in Ras signaling pathway genes (e.g., Rac Family Small GTPase 3, RAC3, and phospholipase A2 group IIA, PLA2G2A). The research was funded by: Servier Laboratoires Keywords: Aggressive B-cell non-Hodgkin lymphoma, Aggressive T-cell non-Hodgkin lymphoma, Combination Therapies No conflicts of interests pertinent to the abstract.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Previous reviews of phase 1 trials in oncology have reported a treatment response rate of 4%–6% and a toxicity-related mortality rate of 0.5%. These results may not reflect current Phase 1 trial rates for patients with lymphoma. Methods: All non-pediatric phase 1 trials for relapsed or refractory (R/R) lymphoma approved by the Cancer Therapy Evaluation Program of the Institut Gustave Roussy between 2008 and 2023 (cut-off date 05 January 2023) were reviewed. We reported on overall survival (OS), treatment response rates, treatment-related deaths, and the number of patients who benefit to have received a drug in clinical trial which was further approved by the health authorities (FDA or EMA). Results: We analyzed 50 trials involving 447 participants (pts) with R/R lymphoma who received at least one dose of treatment. All patients were assessed for toxicity and 382/447 (85%) for treatment response. The median (range) age of patients was 64.9 (19.2–88.5) years. The median of treatments received before entering the trial was 3 (1–13). The main types of lymphoma were DLBCL (n = 253; 56.6%), PTCL (n = 45; 10.1%), Hodgkin (n = 40; 8.9%) and FL (n = 39; 8.7%). The overall response rate (i.e complete and partial responses) was 23.6%. Drug classes in trials included epigenetic modifiers (n = 99 pts; 22.1%), Proteolysis Targeting Chimeras (PROTAC) (n = 90; 20.1%), IO (n = 77; 17.2%), anti-apoptotic inhibitor (n = 50; 11.2%), molecular targeted therapy (n = 46; 10.3%), T-Cell Engagers (n = 23; 5.1%), antibody drug conjugated (n = 20; 4.5%), monoclonal antibody (n = 17; 3.8%), cycle cellular inhibitor (n = 8; 1.8%), gamma secretase inhibitor (n = 8; 1.8%), chemotherapy (n = 5; 1.1%), antiangiogenic (n = 4; 0.9%). Trials including drug further approved by health authorities involved 84/447 (18.8%) of patients and had an overall response rate of 32.9% (26/79 evaluable pts). The overall rate of deaths due to toxic events was 0.45% (2/447 pts). The median OS of patients was 14.1 (CI95% 11.7–17.9) months, with significant variation among lymphoma types (p < 0.0001) (Figure 1). Poor OS was observed for patients with relapsed or refractory with peripheral T-cell lymphoma (8.9 months CI95% 6.9–9.6) (Figure 1). Overall survival of patients with relapsed or refractory lymphoma included in phase 1 trials from 2008 to 2023, according to the lymphoma type (CLL = Chronic lymphoid leukemia; DLBCL = Diffuse large B cell lymphoma; FL = Follicular lymphoma; MCL = Mantle cell lymphoma; MZL = Marginal zone lymphoma; WD = Waldenstrom disease; PTCL = Peripheral T cell lymphoma). Conclusion: Overall response rates among phase 1 trials for patients with R/R lymphoma are higher than those reported with phase 1 in oncology. Toxicity-related mortality rates are similar those reported with phase 1 in oncology. The research was funded by: Ideogen (funding for clinical data analysis) Keywords: Aggressive B-cell non-Hodgkin lymphoma, Aggressive T-cell non-Hodgkin lymphoma, Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. J. M. Michot Honoraria: Ideogen (clinical data analysis)

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Angioimmunoblastic T cell Lymphoma (AITL) is a subtype of peripheral T cell lymphoma and prognosis is generally felt to be poor. Molecular characteristics differentiating good or poor risk AITL has not been identified. In our Asian multicentre study, we investigate the clinical prognostic factors affecting the outcomes of our AITL patients. We also interrogate the gene expression profiles in our patients to identify if there may be different immune and cell signalling signatures in different risk groups. Methods: Patients who were diagnosed with AITL and seen at National Cancer Centre Singapore, Singapore General Hospital and National University Cancer Institute, Singapore between June 1999 and December 2019 were retrospectively analysed. Relevant demographical and clinical characteristics were collected. Outcomes of interest were that of 5-year overall survival (OS) and 5-year progression free survival (PFS). Kaplan-Meier curves were plotted to estimate survival for each individual clinical parameter. Parameters found to be significant on univariate analysis were subsequently used in the generation of multivariate cox regression models. NanoString PanCancer IO360 panel (NanoString Technologies, Seattle, WA, USA) was used to interrogate gene expression on AITL FFPE tissue, following manufacturer’s protocol using the nCounter platform. Results: A total of 174 patients were identified. Median duration of follow up was 20.4 months. Median PFS and OS was 1.8 years and 5.6 years respectively. In multivariate analyses, Age >60, bone marrow Involvement, Total white cell count and serum Lactate dehydrogenase were associated with poorer PFS and OS. A prognostic index (AITL-PI) differentiated patients into low (0–1 factors, n = 64), moderate (2 factors, n = 59) and high-risk (3–4 factors, n = 49) subgroups with 5-year OS of 84.0%, 44.0% and 28.0% respectively (p < 0.0001). Gene expression studies performed in 23 patients found disparate immune cell type profiles and oncogenic signalling pathway signatures in the low risk as compared to the intermediate and high-risk groups. In the low risk group, neutrophilic, T-regulatory and Th-1 cell profiles were predominant whereas cytotoxic cell profile was predominant in the intermediate and high-risk groups. The low risk group was more active in the myeloid compartment, WNT, cytokine and chemokine, TGF-β and hedgehog signalling pathways whereas cytotoxicity, interferon and lymphoid compartment signalling signatures returned higher in the intermediate and high-risk groups. The research was funded by: NCCS Cancer Fund (Research) (NCCSCF-R-YR2021-JUN-SSD1), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore Ministry of Health’s National Medical Research Council Research Transition Awards (TA21jun-0005 and TA20nov-0020), Large Collaborative Grant (OFLCG18May-0028), and Collaborative centre grant (TETRAD II). Keywords: Aggressive T-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers No conflicts of interests pertinent to the abstract.

OPTIMISING HOLISTIC CARE OF WOMEN AT RISK OF OR LIVING WITH BIA‐ALCL: A SURVEY OF UK HEALTH CARE PROFESSIONALS

Introduction: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) was classified by the World Health Organisation in 2016. As of December 2021 there have been 86 reported cases within the UK. Raising awareness amongst clinicians of this novel entity is crucial in order to provide effective clinical care. Psycho-social support forms a vital arm of care, both for affected women but also for the now millions at risk or those considering new implants. This survey aims to assess the current awareness and experiences of health care providers potentially involved in the care of patients with BIA-ALCL with a particular focus on psycho-social support requirements. Methods: We performed an online survey using categorical and open-ended questions. The questionnaire was distributed amongst professional associations that have an interest in the topic researched, e.g., The Association of Breast Surgeons (ABS), British Association of Plastic, Reconstructive and Aesthetic Surgeons (BAPRAS). In addition the survey was distributed amongst multidisciplinary teams that are likely to encounter these patients, e.g. Breast and Lymphoma. The survey was designed in Qualtrics and sent via a link. Data has been collated and analysed within SPSS. Research approval was obtained from Leeds Beckett University. Results: There were a total of 78 respondents who completed the survey. Breast surgeons made up the largest proportion of respondents (36%, 28/78) with over half of respondents having cared for a patient with BIA-ALCL (58% 42/78). The largest proportion of respondents reporting using ABS/BAPRAS joint guidelines in their clinical practice (46%, 36/78). High median confidence scores were reported in both diagnosing/managing, 7/10 (3) and having conversations with patients regarding BIA-ALCL, 7/10 (5) although a large range in responses was noted. The most frequently selected test to work up a case of suspected BIA-ALCL was ‘core biopsy of any associated peri-implant mass’ (82%, 64/78) with mammography the least selected (42%, 33/78). 45% (35/78) reported seeing women requesting reassurance or implant removal despite an absence of symptoms or signs of BIA-ALCL. The average degree of distress upon receiving a diagnosis was reported as 7/10 (2). 70% (54/77) of respondents felt patients diagnosed with BIA-ALCL or those awaiting test results would benefit from psychological support. Only 38 (29/76) % of respondents however, confirmed that breast implant patients have access to any psychological support as part of routine care. Conclusion: This survey demonstrates that although there is relatively high confidence in managing and conducting discussions with patients regarding BIA-ALCL, there is a large variability amongst healthcare providers. The findings suggest there is urgent need for psycho-social support for both patients diagnosed with BIA-ALCL and asymptomatic women seeking reassurance. Keyword: Aggressive T-cell non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract D. Cunningham Consultant or advisory role Ovibio on scientific advisory board Research funding: Medimmune/AZ, Clovis, Eli Lilly, 4SC, Bayer, Celgene, Roche - institution recipient

CLONAL ARCHITECTURE OF RELAPSED OR REFRACTORY FOLLICULAR HELPER T‐CELL LYMPHOMA: AN ANCILLARY STUDY OF THE ORACLE TRIAL, A LYSA STUDY

Follicular helper T-cell lymphoma (TFHL) results from the oncogenic transformation of a TFH cell, driven by mutations in genes involved in epigenetic regulation (TET2, DNMT3A, IDH2) and T-cell signaling (RHOA). Demonstration of TET2 and DNMT3A mutations in B cells, myeloid cells, or hematopoietic progenitor cells have suggested that TFHL can emerge from clonal hematopoiesis (CH) in a multi-step process. However, the frequency, the extension, and the relevance of such CH in TFHL oncogenesis are unclear. To describe and characterize the clonal architecture of refractory/relapsed (R/R) TFHL, we collected bone marrow samples of patients included in the ORACLE trial (NCT03593018), a phase 3 trial evaluating the oral 5-azacitidine (CC-486) compared to single-agent chemotherapy in patients with R/R TFHL. Bone marrow (BM) cells from 32 patients at inclusion were cultured in methylcellulose supplemented with standard growth factors. BFU-E, CFU-GM, and CFU-GEMM were counted and individually harvested. A total of 517 colonies derived from the 32 patients were then individually genotyped by next-generation sequencing (NGS) using a capture-based panel (limit of detection: 1%) covering 43 genes recurrently mutated in CH and/or TFHL, including TET2, DNMT3A, IDH2, and RHOA. Meanwhile, bulk BM cells from 29 patients were sequenced with the same NGS panel and then compared to the mutations found in cfDNA (31 patients) and tumor biopsies (28 patients). Overall, the frequency of CH and the phylogenetic link between the myeloid progenitors and the TFHL was evaluable in 30 TFHL patients. We successfully genotyped 471/517 (91%) colonies. CH defined by at least one somatic mutation detected in at least one myeloid colony or total BM cells was found in 29/30 (97%) patients. Among the 26/29 patients with mutated myeloid colonies, the median percentage of mutated colonies was 21% (IQR 7%–53%) and 7 had subclonal architecture with a median of 3 different clones. The 2 most frequent mutations were DNMT3A and TET2, detected in 24/30 (80%) and 18/30 (60%) patients' BM, respectively. We confirmed the absence of RHOAG17V and IDH2R172 mutations in BM cells of TFHL patients. While 17/18 patients with a detectable TET2 mutation in CH had a TET2 mutated TFHL, only 13/23 patients with a DNMT3A mutated CH had a DNMT3A mutated TFHL. We thus identified 3 groups of patients according to the distribution of mutations found in the BM and the LN lymph nodes: 16/30 (53.3%) patients had a TFHL clonally derived from CH (CH-related TFHL), 13 (43.3%) had TFHL, and clonally distinct CH (CH-unrelated TFHL), and one patient (3.3%) had undetectable CH. No significant difference in patient outcome was observed regarding the presence of CH-related or unrelated TFHL, but our results are limited by the small number of patients and treatment heterogeneity. Encore Abstract—previously submitted to EHA 2023 Keywords: aggressive T-cell non-Hodgkin lymphoma, tumor biology and heterogeneity No conflicts of interests pertinent to the abstract.

Distribution of non-Hodgkin lymphomas across US: Are Hispanics any different from non-Hispanics?

e18619 Background: Non-Hodgkin lymphoma (NHL) encompasses various subtypes that differ in incidence, etiology, clinical features, and survival. NHL subtypes can be divided into B-cell and T-cell lymphomas, when classifying them based on cell of origin. The distribution of NHL subtypes has been known to variate between geographic locations, and always results are reported without classifying them among ethnicities. Hispanics are by now, the largest ethnic minority in US, according to the latest 2020 US Census, and it is of utmost importance to understand variations related to ethnicity. This is to our knowledge, the largest retrospective study comparing NHL frequency of subtypes in Hispanics vs Non-Hispanics. Methods: Data were analyzed on NHL patients in the US and reported to the Surveillance, Epidemiology, and End Results (SEER) 18 database between 2000 and 2018. SEER 18 contains the most comprehensive population-based cancer information in the US, covering approximately 27% of the US population and up to 36% of HI alone. Racial groups analyzed included NH whites and HI whites. Results: There were 366516 patients diagnosed with NHL over the 8-year study period included in our study. Most of these patients belong to the B-cell NHL type, comprising 91% of the group. The distribution of the major subtypes of NHL is shown in the pie charts. We noted differences in the distribution of major NHL subtypes among NH and H. Among the B-Cell NHL subtypes, Hispanics had higher proportions of DLBCL (42% vs. 31%), FL (19% vs. 17%), and Burkitt lymphoma (4% vs. 2%) than NH. On the contrary, a significant difference was found, with a higher presence of CLL/SLL in NH, which was seen in 31% vs. 15% in H. Within the T-Cell NHL subtypes, compared with non-Hispanics, Hispanics had higher proportions of NK/T cell lymphoma (11% vs. 3%) and anaplastic large cell lymphoma (15 vs. 12%) but a lower proportion of mycosis (26% vs. 30) in NH and cutaneous T-cell lymphoma (9% vs. 13%). The rest of the subtypes showed to have similar proportion rates. Conclusions: In conclusion, our study shows evidence of a significant difference in subtype distribution between NH and H patients. The involvement of a complex process in developing NHL and the etiologic heterogeneity among subtypes has been previously described. These differences in subtype distribution across races may be due to geographic location, genetic variants, occupational exposures, infectious conditions, family history, and socioeconomic status. Analyzing and comparing multiple cancer subtypes can provide critical clues for future epidemiological investigations to improve care among our minorities. Due to the growing Hispanic population in the US, it is significantly vital to represent the differences in subtype presentation graphically.