Aggressive T-cell non-Hodgkin Lymphoma Research Articles

Abstract 4320: Interrogation of autophagy inhibition in anaplastic large cell lymphoma (ALCL)

Abstract The objectives of this study are to evaluate if anaplastic lymphoma kinase (ALK) inhibition activates autophagy in ALK+ ALCL cells and to determine if that activation can be mitigated using autophagy inhibition. ALCL is an aggressive T-cell non-Hodgkin lymphoma that often presents as advanced stage disease. With the addition of crizotinib or brentuximab vedotin to the ALCL99 chemotherapy backbone, the recently reported Children’s Oncology Group ANHL12P1 study demonstrated a 2-year event-free survival for ALCL patients of 79%. Thus, even with multi-agent chemotherapy combined with targeted therapy, improved therapeutic efficacy is needed. Autophagy is activated when mTORC1 is inhibited, and as ALK signaling is known to promote mTORC1 activity, ALK inhibition is hypothesized to activate autophagy. If present, ALK inhibitor-induced autophagy activation would represent a novel therapeutic opportunity targetable with emerging autophagy inhibitors. An ALK+ ALCL cell line, Karpas 299, was treated with drug combinations for 3 hours, lysates prepared, and proteins separated by molecular weight using standard procedures. ALK inhibitor target engagement was assessed by western blot using phospho-ALKY1604 intensity in 9-point dose response curves. Target engagement of autophagy inhibition (ULK-101 directed against ULK1/2 and hydroxychloroquine (HCQ) targeting the lysosome) was assessed by western blot using phospho-ATG14S29 and LC3B-II intensity in 6-point dose response curves. Cell viability was evaluated using a luminescent CellTiter-Glo assay. Karpas299 cells resistant to crizotinib at 50nM (KCrizR50) were generated by gradually increasing crizotinib concentration in the media until cells grew at a rate similar to parental cells. Crizotinib, ceritinib, and lorlatinib all effectively inhibit ALK phosphorylation in Karpas 299 cells with low nanomolar potency. ULK-101 effectively inhibited pATG14S29 at 5 µM and HCQ effectively inhibited autophagic flux, as evidenced by increased LC3B-II intensity, at 20 µM. When treated with the lowest ALK inhibitor dose needed to achieve complete pALK inhibition (IC99), pATG14 intensity increased representing increased autophagic activity. When combined with ALK inhibition, ULK-101 effectively decreased pATG14S29, blocking the ALK inhibitor-induced autophagy activation. Decreased viability in Karpas 299 cells was observed after crizotinib, ceritinib and lorlatinib treatments with nanomolar potency. KCrizR50 cells had a potency higher than parental Karpas 299 cells for all three ALK inhibitors. ALK inhibition activates autophagy in ALCL cells and autophagy activation is effectively mitigated through concurrent autophagy inhibition. ALK inhibitor resistance in Karpas 299 cells will be further evaluated to determine whether autophagy contributes to the resistant phenotype. Citation Format: Katie L. Buelow, Stephanie Celano, Gregory Poole, Katie Martin, Jeffrey MacKeigan, David J. Hoogstra. Interrogation of autophagy inhibition in anaplastic large cell lymphoma (ALCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4320.

Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma.

EATL is an aggressive T-cell non-Hodgkin lymphoma with poor prognosis and is largely localized to the small intestine. EATL is closely associated with coeliac disease (CD) and is seen mostly in patients originating from Northern Europe. Various factors are associated with an increased risk of developing EATL, such as viral infection, advanced age, being male, and the presence of the HLA-DQ2 haplotype. Clonal rearrangements in the TCR-β and γ genes have been reported in all EATL morphological variants with distinctive immunophenotypic characteristics. Although EATL can occur de novo, individuals with RCDII are at a higher risk of developing EATL. The cells of origin of EATL has been postulated to be normal small intestinal intraepithelial T-lymphocytes (IELs), and more recent evidence suggests a link between innate precursor IELs and EATL derived from refractory coeliac disease type II (RCDII). The immune microenvironment of mucosal cells within the small intestine enhances the process of neoplastic transformation of IELs into EATL. Cytokines such as IL-15 can activate and crucially deregulate the JAK-STAT signaling pathway by binding to receptors on the surface of IELs. Furthermore, mutations in the JAK/STAT pathway have been associated with RCDII-derived EATL.

CLINICAL EFFICACY OF CD34 POSITIVE SELECTION EX‐VIVO PURGING DURING AUTOLOGOUS STEM CELL TRANSPLANTATION IN PERIPHERAL T CELL LYMPHOMA

Background: Autologous stem cell transplantation (ASCT) is the standard treatment for peripheral T-cell lymphomas (PTCLs). Strategies that reduce the relapse rate and treatment-related mortality are essential for successful ASCT. Because in vivo/in vitro purging methods using rituximab are not appropriate for T-cell lymphomas, an ex vivo CD34+ selective purging system using CliniMACS is the most reliable method to reduce autograft tumor cell contamination in these tumors. In the present study, we retrospectively analyzed the clinical outcomes of HDT/ASCT after ex vivo purging via the CD34+ selective method in T-cell NHL patients. Methods: We retrospectively investigated the influence of ex vivo purging with CD34+ selection to maximize the effects of ASCT. Of 67 consecutive PTCL patients, 32 and 35 underwent purged and unpurged ASCT. Results: The purged group had improved overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (hazard ratio [HR] = 2.68, p = 0.016; HR = 3.97, p = 0.002; and HR = 3.65, p = 0.004, respectively), compared to the unpurged group. Prognostic factor analysis showed that unpurged ASCT, chromosomal abnormalities at initial diagnosis, high risk, and pre-ASCT disease status were associated with poor survival outcomes. Subgroup analysis demonstrated that purging was most appropriate for International Prognostic Index high-risk patients who underwent upfront ASCT (HR = 3.35 [OS] and = 6.59 [DFS]). In purged ASCT group, NK cell activity and the lymphocyte-to-monocyte ratio known as an independent prognostic factor were increased after ASCT with statistical significance; the lymphocyte-to-monocyte ratio (LMR) was significantly increased after ASCT in the purged group (mean difference = 1.484, 95% CI = 0.407–2.560; p = 0.009). Also, Engraftment was achieved in all patients with no need for unpurged autologous stem cell backup in purged group. There were no engraftment failures or differences in adverse events including of transplant-related viral infections between the two groups. The research was funded by: The research was funded by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2020R1G1A1099654). Keywords: Aggressive T-cell non-Hodgkin lymphoma, Stem Cell Transplant No conflicts of interests pertinent to the abstract.

BRENTUXIMAB VEDOTIN IN COMBINATION WITH CHEMOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED CD30‐POSITIVE PERIPHERAL T‐CELL LYMPHOMAS: REAL‐WORLD DATA

Background: Based on the results of ECHELON-2 trial, Brentuximab vedotin (BV) in combination with cyclophosphamide, doxorubicin and prednisone (CHP) has been approved by EMA for the treatment of newly diagnosed systemic anaplastic large cell lymphoma (ALCL) and become the standard of care for this patient population. In Czech Republic, BV plus CHP is approved as 1st line treatment for CD30-positive peripheral T-cell lymphomas (PTCL), including non-ALCL PTCL since 8/2020. The aim of this analysis is to provide real world data with this combination. Methods: Using the prospective observational NiHiL project (NCT03199066), we identified patients (pts) ≥ 18 years of age with histologically confirmed CD30+ PTCL (diagnosed between August 2020 to October 2022), who received BV in combination with chemotherapy as 1st line treatment. Results: A total of 63 pts were recruited; 31 (49%) had ALCL (12 ALK+, 19 ALK-) and 32 (51%) had non-ALCL PTCL (16 with PTCL NOS, 14 with AITL, and 2 with EATL). Median age was 60 years (range; 19-82). Most pts showed adverse clinical features at lymphoma diagnosis, including Ann Arbor stage III-IV (n = 46; 73%) or elevated LDH (n = 34; 54%). Of note, 18 (29%) pts had ECOG performance status ≥ 2 (incl. 6 pts ECOG 3 and 1 pt ECOG 4). By IPI, 16 (25%), 18 (29%), 12 (19%), and 17 (27%) pts belonged to low, low-intermediate, high-intermediate, and high-risk groups, respectively. The most common chemotherapy backbone was CHP administered in 45 (71%) pts, followed by CHP + etoposide administered in 13 (21%) pts. Five (8%) pts received attenuated regimen. Nine (14%) pts underwent pre-planned consolidative autologous stem cell transplant. Sixty (95%) pts received G-CSF prophylaxis. The most common grade ≥3 adverse events were neutropenia (49%), anaemia (30%), febrile neutropenia (19%), thrombocytopenia (19%), and infections (18%). Neuropathy (all grades) occurred in 21 pts (33%); grade 3 neuropathy in 3 pts (5%). Grade 5 AE occurred in 2 (3%) pts, sepsis in both cases. Out of 63 there were 56 (89%) pts evaluable for response (PET/CT) at the time of database lock. The overall objective response rate (ORR) was 80% with 63% complete response (CR). The ORR/CR rates in ALCL (n = 26) versus non-ALCL (n = 30) pts were 89%/73% versus 73%/53%, respectively. The median follow-up of surviving pts is 16.6 months (range; 4.3- 31.3). The overall 18-months PFS and OS probability were 61.8% and 73.7%, respectively (Figure 1). By lymphoma subtype, the 18-months PFS and OS probability were 77.6% and 83.5% in ALCL and 50.3% and 65.9% in non-ALCL, respectively (Figure 1). Evaluation of the relationship between % of CD30+ neoplastic cells and clinical outcome is ongoing. The research was funded by: The study is supported by the Cooperation Program, research area “Oncology and Haematology” and NU20-03-00253 and NU22-03-00370. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Combination Therapies Conflicts of interests pertinent to the abstract A. Sykorova Other remuneration: ROCHE, GILEAD, TAKEDA H. Mocikova Consultant or advisory role Takeda, Roche, Astra Zeneca, Janssen, Abbvie D. Belada Other remuneration: Roche, Gilead Sciences M. Trneny Consultant or advisory role Takeda Honoraria: Takeda

GOLIDOCITINIB IN TREATING REFRACTORY OR RELAPSED PERIPHERAL T‐CELL LYMPHOMA: PRIMARY ANALYSIS OF THE MULTINATIONAL PIVOTAL STUDY RESULTS (JACKPOT8)

Introduction: Currently there is no consensus on the treatment of relapsed/refractory (r/r) PTCL, and patient prognosis was poor. Golidocitinib is an orally available, JAK1-selective inhibitor currently being evaluated in a multinational, pivotal study in r/r PTCL (JACKPOT8 Part B, NCT04105010). Here we reported the primary analysis of efficacy and safety results of this study. Methods: PTCL patients who had relapsed from or had been refractory/intolerant to ≥1 (but ≤3) prior systemic therapy(ies) were enrolled to receive golidocitinib at 150 mg once daily until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was CT-based objective response rate (ORR) assessed by an independent review committee (IRC) according to Lugano 2014 classification. The efficacy analysis set included patients whose pathological diagnosis of PTCL had been retrospectively confirmed by a central laboratory and who had at least one measurable lesions at baseline. The safety analysis set included all dosed patients. Results: As of 30 November 2022, a total of 104 patients with r/r PTCL were enrolled and dosed with golidocitinib. Baseline characteristics: median age was 58 yrs; 64.4% were male; 20.2% had baseline bone marrow involvement. Major subtypes included NOS (46.2%), AITL (15.4%) and ALCL (9.6%). The median prior lines of therapies were two. All of the patients had been treated with chemotherapies, and 48.1% had been treated with histone deacetylase inhibitors. By the data cut-off (DCO) date, a total of 80 patients had both IRC assessment and central pathology review results available, and thus were included in the efficacy analysis. Among them, 35 patients achieved tumor response (ORR = 43.8%), including 20 patients (25.0%) achieved complete responses. Tumor response was observed in various subtypes, including AITL (56.3%), NOS (45.7%), ALCL (11.1%) and others (44.4%). In patients who relapsed from HDAC inhibitor treatment, 54.8% achieved tumor response. With a median follow-up of 5.5 months for responders, the median duration of response (DoR) has not been reached. Golidocitinib was tolerated in patients with r/r PTCL. By the DCO date, the longest duration on treatment was 15.7 months (still responding). The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hematological in nature, including neutrophil count decreased (26.0%), white blood cell count decreased (25.0%), platelet count decreased (16.3%) and lymphocyte count decreased (16.3%). TRAEs leading to dose interruption, reduction, and discontinuation were 37.5%, 5.8%, and 7.7%, respectively. The majority of TRAEs were reversible or clinically manageable. Conclusions: Golidocitinib demonstrated its potential as a novel targeted therapy for the treatment of r/r PTCL. The updated data will be presented at the conference. Encore Abstract—previously submitted to ASCO 2023 Keywords: aggressive T-cell non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract W. Yu Employment or leadership position: Employed by Dizal Pharmaceutical

PROGNOSTIC SIGNIFICANCE OF SEQUENTIAL 18F‐FDG PET/CT DURING THE TREATMENT OF ANTHRACYCLINE‐CONTAINING FRONTLINE CHEMOTHERAPY IN PERIPHERAL T CELL LYMPHOMAS

Introduction: Despite the prognostic significance of 18F-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET/CT) assessment has important implications on determining the response-adapted therapy in patients with peripheral T-cell lymphomas (PTCLs), an optimal timing of the use and clinical application of PET/CT-based response are still up in the air. The aim of this study was to explore the prognostic impact of sequential 18F-FDG PET/CT analysis in patients with newly diagnosed PTCLs who treated with frontline anthracycline-based chemotherapy. Methods: Between February 2006 and September 2022, 143 patients with newly diagnosed PTCLs were included. All patients were treated with 6 cycles of anthracycline-containing chemotherapy. Sequential 18F-FDG PET/CT were obtained at the time of diagnosis, after three cycles of chemotherapy and finally at the end of chemotherapy. Baseline total metabolic tumor volume (TMTV) was computed with the sum of SUV2.5 threshold method, and the PET/CT response were assessed using the five-point scale (5-PS) of Deauville criteria. Results: Baseline MTV could be calculated in 126 patients, and the cut-off value of TMTV according to ROC analysis was 457.0 cm3 (Sensitivity 45.0%, specificity 74.0%). With a median follow-up of 52.0 months (range 3.8–153.9 months), patients with high TMTV more than cut-off value had inferior PFS and OS than those with low TMTV (PFS, 9.8 months vs. 26.5 months, HR 1.600, 95% CI 1.010–2.671, p = 0.043; OS, 18.9 months vs. 71.2 months, HR 2.135, 95% CI 1.261–3.615, p = 0.004, Figure 1A, B). Interim 18F-FDG PET/CT assessment was available in all 143 patients. When patients were categorized with three subgroups as response with grade 1, grade 2 and 3, and grade 4–5, PFS and OS showed significant difference according to interim visual assessment (PFS, 120.7 months vs. 34.1 months vs. 5.1 months, p < 0.001; OS, not reached vs. 61.1 months vs. 12.1 months, p < 0.001, Figure 1C, D), respectively. Among 77 patients who were assessed as grade 2 or 3 in interim PET/CT analysis, 19 patients (26.3%) turned over a remnant tumor metabolism or progressed at final PET response assessment. Moreover, the outcome of patients with interim grade 2 or 3 showed the significant differences based on the final achievement of complete metabolic response or not in PFS and OS (PFS, 59.9 months vs. 7.2 months, HR 4.754, 95% CI 2.267–9.971, p < 0.001; OS, not reached vs. 24.0 months, HR 3.706, 95% CI 1.592–8.630, p = 0.001), respectively. Keywords: aggressive T-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers No conflicts of interests pertinent to the abstract.

Molecular features possessed in the ctDNA reveal heterogeneity and predict outcome in newly diagnosed peripheral T‐cell lymphoma

Introduction: Circulating tumor DNA (ctDNA) has been proven to be a promising tumor-specific biomarker in tumors, but its clinical utility in risk stratification and early prediction of relapse for peripheral T cell lymphoma (PTCL) has not been well explored. Methods: Using a lymphoma-specific sequencing panel, we assessed the prognostic and predictive utilities of ctDNA measurements before and after first-line therapy in 41 PTCL patients. Results: For the 41 patients, we obtained a total of 36 primary tumor specimens, 41 pretreatment blood samples and 21 serial blood samples before and after first-line therapy. By the last visit in March 2023, the median follow-up duration was 10.0 (range, 2.5–18.8) months. The clinical characteristics of the 41 patients were shown in Figure 1A. All patients received CHOP-like regimen. The top 30 somatic mutations of tissues were shown in Figure 1B. Pretreatment ctDNA (Pre-ctDNA) achieved an overall sensitivity of 81.3% (159/196) in detecting variants verified in tumor, indicating that ctDNA is a reliable source for PTCL genotyping. In addition, ctDNA allowed for the identification of additional 98 somatic mutations that were undetectable in tumor gDNA, which demonstrated that ctDNA could overcome tumor spatial heterogeneity (Figure 1C). Pre-ctDNA burden was significantly associated with clinical characteristics, including extranodal involvement (P < 0.001), lactate dehydrogenase (LDH) levels (P < 0.001), age (P = 0.047), B symptoms (P = 0.038), stage (P = 0.008) and international prognosis index (IPI) score (P < 0.001) (Figure 1D). The cell-free (cfDNA) fragments profoundly reflects both genomic and chromatin characteristics. Our results suggested that all samples had a more prominent mono-nucleosomal fragments abundance (167 bp), whereas the samples of angioimmunoblastic T-cell lymphom (AITL) and the samples with high IPI scores or non-complete response (CR) in the mid-stage of treatment had a more prominent shift towards shorter cfDNA size (Figure 1E). Similarly, when we analyzed the response to treatment, significant decline in ctDNA levels was observed at end of treatment (EOT) in patients with CR compared with those who did not achieved CR. The 4 patients with CR and EOT ctDNA negative achieved continuous CR until now (Figure 1F). Furthermore, high pre-ctDNA levels presented unfavourable PFS (P = 0.002) and OS (P = 0.020) (Figure 1G). Multivariate cox regression analysis showed that high pre-ctDNA burden (P = 0.029) and TP53 mutation (P = 0.005) (Figure 1H). Subgroup analysis showed that patients without these 2 risk factors (Type 1) had longer PFS than the other patients with more than 0 risk factor (Type 2) (P < 0.001) (Figure 1I). Keywords: Aggressive T-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers No conflicts of interests pertinent to the abstract.

ANALYSIS OF PATIENTS IN THE FIRST RELAPSE OR PROGRESSION OF T‐CELL LYMPHOMA. REAL WORLD DATA FROM CZECH LYMPHOMA STUDY GROUP REGISTRY (NIHIL).

Background: Systemic T-cell lymphoma (TCL) is heterogeneous group of hematological malignancies with extremely poor prognosis. The prognosis of relapsed/ progressed disease is much worse, but there are sporadic data about this group of patients only. We focused on the most frequent subsets ALCL, PTCL-NOS and AITL/TFH-TCL) representing around 70% of all systemic T-cell lymphoma. Methods: For this analysis, ALCL, PTCL-NOS and AITL patients at first progression (n = 441) were selected from the NIHIL registry (initial diagnosis 1999-2021). We tried to characterize this group of patients by calculation of PFS, OS, OS2 and interval from-relapse-to-therapy. We compared the subgroup of patients with early vs. late progression. Results: At the first relapse (R1), there were 117 (26.5%) ALCLs, 74 (16.8%) AITLs, and 250 (56.7%) PTCLs, median age was 63 yrs (range; 19-91); 274/441 (62%) were men. First-line therapy included CHOP (254; 57.6%), CHOEP/CEP (110; 24.9%), and 52 (11.8%) pts were autotransplanted. Median since diagnosis to R1 was 0.72 yrs (range; 0.3–15.2), median OS2 from progression was 0.41 yr (0–10.28). Majority of patients 293/441 (66%) progressed early within 1 year including 168 (57%) of primary progression, whereas 58 (13%) pts only relapsed 2.5 years or later, remaining 90 (20%) pts relapsed between 1 and 2.5 years. Patients with early relapse (<1 year) with median age (61 yrs), 65% were men, median OS2 was 0.31 year (0-8.9); median interval from-relapse- to-therapy was 8 days (range; 0-370). The most frequent therapy administered in R1 were platinum-based (28%) a gemcitabine-based (16%) regimen, 40 (13.6%) pts were transplanted (including 20 alloTx); whereas 26% patients did not start any therapy. Patients with late relapse (≥2.5 years) had median age 65 yrs, 55% were men, OS2 was longer with median 0.97 year (range; 0.05-10.2); median interval from-relapse- to-therapy was longer with median 34 days (range; 0-273). The patients were treated by gemcitabine (28%) and platinum-based regimens (22%), whereas 17% patients were not treated at all, autoTx was administered in 14% cases. Conclusions: Our analysis demonstrates that relapse of TCL is usually fatal event for majority of patients with very short survival (in order of months), which occurs very early (in two thirds of pts within 1 yr since diagnosis). Because of lack of data from big clinical trials, these results could serve as a supporting evidence for administration of case-driven targeted therapy. Conflicts of interests pertinent to the abstract Keywords: Aggressive T-cell non-Hodgkin lymphoma, Non-Hodgkin (Pediatric, Adolescent, and Young Adult) D. Belada Consultant or advisory role Gilead, Roche, Novartis, Takead 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

PRELIMINARY RESULTS OF GEMCITABINE, ETOPOSIDE, MITOXANTRONE HYDROCHLORIDE LIPOSOME AND DEXAMETHASONE REGIMEN FOR NEWLY DIAGNOSED EARLY NUAT OR ADVANCED STAGE ENKTL

Introduction: Extra-nodal NK/T-cell lymphoma (ENKTL) is an aggressive disease common in Asia but rare in the West. More than two-thirds of persons have stage I/II disease of the upper aero-digestive tract (UAT), which have relatively superior prognosis. However, patient of early non-UAT (NUAT) or advanced stage show an aggressive clinical course with extremely poor prognosis and low survival rates. Mitoxantrone hydrochloride liposome has reported to have efficacy in relapsed/ refractory (R/R) ENKTL in a phase II clinical trial. Furthermore, patient of early NUAT or advanced stage always have hemophagocytic lymphohistiocytosis (HLH) at diagnosis. Therefore, etoposide and high dose dexamethasone were also important for these patients. Based on these facts, this study evaluates the efficacy and safety of the regimen of gemcitabine, etoposide, mitoxantrone hydrochloride liposome, and dexamethasone (P-GEMD) in patients of newly diagnosed early NUAT or advanced stage ENKTL. Methods: Patients diagnosed as ENKTL in early NUAT and advanced stage form 18‒80 years with ECOG of 0‒2 were eligible for enrollment. We planned a maximum of 6 cycles of P-GEMD regimens for patients. The P-GEMD regimen was administered intravenously every 3 weeks until disease progression (PD) or unacceptable toxicity as follows (Figure 1A): pegaspargase at 2500 IU/m2 d2; gemcitabine at 1000 mg/m2, d1; etoposide at 65 mg/m2, d2‒4; mitoxantrone hydrochloride liposome at 12 mg/m2, d1; dexamethasone at 40 mg/d, d1‒4. The primary endpoint is complete response rate (CRR). The second endpoint are overall response rate (ORR), duration of response (DOR) and 1-year overall survival (OS) and progression-free survival (PFS). Results: Five patients were preliminarily planned for P-GEMD regimens. Median age was 51y (range 44‒60 y). All the five patients were advanced stage with B symptoms. The median PINK and PINK-E score was 2 (range 2‒4) and 3 (range 3‒4), respectively. Two patients experienced HLH at diagnosis. All the five patients completed the induction of P-GEMD regimens with the median cycles of 6 (range 3‒6). Only 1 patient experienced PD while the other 4 patients were evaluated as CR by PET-CT. Therefore, the CRR is 80% (Figure 1B). Furthermore, the 4 patients with CR evaluated by PET-CT were all negatively for minimal residual disease (circulating tumor DNA) checked by next generation sequencing (NGS) while the ctDNA burden of patient with PD was positive (Figure 1C-G). There were 30 adverse events (AEs) recorded, of which 86.7% were grade 1 or 2. Hypo-fibrinogenemia, hypo-albuminemia and asparate transaminase increase were the most common grade 3 or 4 AEs (Figure 1H). Keywords: Aggressive T-cell non-Hodgkin lymphoma, Chemotherapy, Combination Therapies No conflicts of interests pertinent to the abstract.

CHROMATIN ACCESSIBILITY PROFILING TO INCREASE DIAGNOSTIC ACCURACY AND REFINE CELL‐OF‐ORIGIN CLASSIFICATION OF MATURE T‐CELL LYMPHOMAS

Mature T-cell neoplasms (MTCN) are heterogeneous diseases with dismal prognosis. Differentiating between the many entities requires specialized pathology expertise, and studies show up to 30% of minor or major diagnostic reclassifications following expert review of cases. Assay for transposase-accessible chromatin sequencing (ATAC-seq) is a simple technique to profile open chromatin regions, which has been shown to be highly discriminative for clustering solid tumors and acute myeloid leukemias. We applied ATAC-seq to MTCN to explore the epigenetic landscape of these different entities, and built a predictive model to aid in diagnosis. FACS-sorted tumor cells from primary MTCN samples and 50µm sections of frozen tumor tissue from the French TENOMIC T-cell lymphoma consortium were processed according to previously published FAST- and OMNI-ATAC protocols, respectively. In parallel, we applied FAST-ATAC to several normal T and NK cell subsets sorted from PBMC or lymph node suspensions of healthy donors. Sequencing data were processed by an adapted version of the ENCODE ATAC-seq pipeline using a custom Hg38 genome version including HTLV1 sequence. A total of 678 normal and tumor samples were sequenced to provide a comprehensive landscape of chromatin accessibility in MTCN. Unsupervised clustering of normal NK and T cell subtypes (N = 49) and sorted tumoral lymphoma cells (N = 104) confirmed that AITL are derived from TFH cells, HSTL and LGL are closely segregated with NK and gd-T cells. We also found that T-PLL likely derive from the transformation of naïve T cells. Epigenetic profiling by ATAC-seq of FACS-sorted tumor samples resulted in a complete segregation of the known MTCN entities (TFH, ALK+ and ALK- ALCL, HSTL, CTCL, ATLL, LGL and T-PLL). Most PTCL-NOS (13/17) clustered with a predefined MTCN subtype (mainly AITL/TFH-phenotype PTCL, CTCL and lymphomas exhibiting cytotoxic features), showing that this waste basket subgroup is merely virtual, at least from an epigenetic point of view. Using unsupervised deconvolution approaches, we were able to discriminate different MTCN subtypes from 223 processed frozen bulk samples. All known MTCN subtypes were identified by ATAC-seq but a novel subset of PTCL-NOS representing ∼5% of cases was pinpointed, showing high GATA3 transcription factor activity. Subsequent exome sequencing revealed numerous copy number alterations and TP53 (8/12) and NCOR1 mutations (7/12). A support vector machine model was trained to predict diagnosis and showed accurate classification performance by cross-validation and on external validation cohort collected from 5 tertiary care centers. ATAC-seq is a rapid and cost-effective technique with high classification accuracy for PTCL subtypes. Among GATA3-expressing PTCL that spread across multiple epigenetic subgroups, we identified a specific entity with recurrent NCOR1 mutations. Keywords: aggressive T-cell non-Hodgkin lymphoma, genomics, epigenomics, and other -omics, pathology and classification of lymphomas No conflicts of interests pertinent to the abstract.

BRCA1/2 MUTATIONS IMPACT ON THE DEVELOPMENT OF BREAST IMPLANT‐ASSOCIATED LYMPHOMA (BIA‐ALCL) IN WOMEN WITH BREAST CANCER RECONSTRUCTED WITH TEXTURED BREAST IMPLANTS

Introduction: Breast Implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a subtype of T-cell lymphoma arising as a seroma and/or mass in relation to the capsule of textured breast implants. Previous research in a Dutch population suggests a higher-than-expected prevalence of BRCA1/2 carriers in women with BIA-ALCL. Here we analyze the risk of BIA-ALCL occurrence related to BRCA in a large population of women with implants followed long term after breast cancer (BC) mastectomy. Methods: We compared the prevalence of BRCA1/2 pathogenic variants (pv) between women from a large cohort of BC patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) who did and did not develop BIA-ALCL after reconstruction with textured implants. Hazard ratios (HRs) of developing BIA-ALCL were estimated using Cox regression. To best control for age at BC diagnosis and length of follow up, we conducted a nested case-control within the cohort, matching 1:3, analyzed with conditional logistic regression. Results: Among 3312 women with BC assessed for pv in the context of MSK-IMPACT tumor and normal study at MSKCC the prevalence of BRCA mutations was 5.3%. Among 526 patients with textured implants post BC mastectomy, followed long term at MSKCC (median FU 82 mo, range 12, 316) and clinically assessed for BRCA1/2, the prevalence of pv of BRCA1/2 was 7.8%. Of 31 BIA-ALCL post-BC cases seen at MSKCC, 16 received capsulectomy at MSKCC and 5/13 (38.4%) were BRCA1–2 positive. Within the cohort of 526 patients with BC tested for BRCA, reconstructed with textured implants and followed long-term, the age-adjusted rate of developing BIA-ALCL for women with BRCA mutations was 11.0 times the rate of BIA-ALCL among women without BRCA (HR 95% CI 3.6, 33.9, p < .0001). Carrying bilateral versus unilateral implants (HR 6.9, 95% CI 0.9, 53.2), prior chemotherapy exposure (HR 0.7, 95% CI 0.2, 2.05), prior radiation therapy exposure (HR 0.5, 95% CI 0.1, 2.5) were not significantly associated with the rate of BIA-ALCL. Within this cohort, 13 BIA-ALCL cases were matched 1:3 with 39 controls. Median ages at BC mastectomy were 47.2 (37, 66) and 46.8 (35, 65) in cases and controls, respectively. The median time between reconstruction for BC and BIA-ALCL was 130 (80, 190) months. The odds ratio of BIA-ALCL associated with carriership of a BRCA1/2 pathogenic variant was 12.4 (Wald 95% CI 1.4, 109.5 p = 0.0074). Conclusions: In this study, we define the role of BRCA1/2 mutations as a significant risk factor in the development of BIA-ALCL in patients with BC reconstructed with textured implants. These results will help decision making for women with BRCA1/2 mutations undergoing breast reconstruction, or with textured implants in place. Analysis of pathogenic variants in other DNA repair genes in this cohort potentially affecting lymphomagenesis is ongoing. The research was funded by: NIH R03 grant number R03CA267435 Keywords: aggressive T-cell non-Hodgkin lymphoma, prevention and cancer interception No conflicts of interests pertinent to the abstract.

PERIPHERAL T CELL LYMPHOMA (PTCL) AND TREATMENT OUT‐COME SINGLE CENTRE RETROSPECTIVE STUDY

Introduction: Mature T-cell lymphomas comprise 15% to 20% of all aggressive non-Hodgkin lymphomas (NHL) and 5% to 10% of all NHLs. Compared to their B-cell counterparts, PTCLs remain largely unexplored and the optimal treatment ill-defined due to disease rarity and biological heterogeneity. CHOP-type chemotherapy has been the mainstay of therapy for PTCL with some exception in NK/T cell lymphoma, but with the notable exception of ALK-positive ALCL, outcome has been uniformly disappointing3-5. For the main nodal PTCLs (AITL, PTCL-NOS, and ALK− ALCL), the 2- and 5-year progression-free survival (PFS) is approximately 35% and 25%, and the 2- and 5-year overall survival (OS) is 45% and 35%, respectively6-8. Progressions/relapses of PTCLs are frequent (approximately 70% of patients), occur most often early (during the first year after initial diagnosis), and have a poor outcome, with a median OS of approximately 6 months 9-11. Methods: Patients were identified through pathology database and informed consent obtained. Patient’s demographic characteristics, clinical features, initial / subsequent treatment and survival were analysed. Data cut-off was 31/01/2023. Results: Twenty-seven patients were included in this study, with male predominance (70%), the median age was 69 years (Rang 17-84 years) and the majority with advanced disease (67%). The common histology subtype was ALCL in 10 patients (37%) (Alk-Neg =7 & Alk-Pos =3) followed by PTCL in 9 patients (33%). While EATL, AITL subtypes were reported in 5(18%), 3(11%) patients respectively. Chemotherapy was the main initial treatment modality in our cohort (26 patients / 96%) (CHOP based /19 patients, CHOEP in 4 patients, and GDP based /3 patients) and 1patient (4%) was not suitable for any therapy. Complete response (CR) was achieved in 16 patients (59%) and 8 patients (30%) subsequently relapsed, while other treated patients (10/37%) experienced disease progression. At relapse GDP and Brentuximab Vedotin therapy were used for in 8 and 3 patients respectively resulted in CR in 2 patients and progression disease in the reminder. Autologous bone marrow transplant consolidation was used in 3 patients (10%), and radiotherapy was used in 5patients (15%). At time of study data analysis (31/01/2023), 8 patients (30%) were still alive and 19 patient (70%) had died mostly lymphoma related death (18 patients). Keywords: Aggressive T-cell non-Hodgkin lymphoma, Pathology and Classification of Lymphomas No conflicts of interests pertinent to the abstract.

Mature T and NK cell lymphomas classified according to 2016 WHO classification. A report of 741 cases registered in the International Prospective T‐cell Project 2.0.

Introduction: Mature T and NK-cell lymphomas represent a heterogeneous group of rare lymphoid disorders arising from mature T cells of post-thymic origin. The T-cell Project 2.0 (TCP2) was launched in 2018 with the aim of better understanding this group of rare disorders, capturing a real-life snapshot of the evolving landscape of T-cell lymphoma biology, treatment strategies, and outcome. Here we report preliminary data on histotype distribution, disease characteristics, front line treatment, and short-term outcome of patients registered between 2018 and 2021. Methods: The TCP2 (ClinicalTrials.gov Identifier: NCT03964480) is a prospective, longitudinal, international, observational study of patients with Peripheral T-cell lymphoma (PTCL). For this analysis we considered cases based on the diagnosis made locally according to the WHO2016 classification. The study was approved by each participating center and required patients to sign informed consent. Results: Between October 2018 and December 2021, 741 eligible cases with newly diagnosed PTCLs were registered by 94 Institutions across 17 Countries. Overall, PTCL-NOS, AITL, ALCL ALK-, ALCL ALK+, ENKTCL, and ATLL resulted the most frequent 6 subtypes, accounting for 91% of cases, while the remaining 9% were represented by few cases of 13 different subtypes. Of note, only 16 cases (2.1%) were classified according to entities not considered in the previous WHO 2008 classification. The median age at diagnosis was 57 years (18–93), 56.5% of patients were male, the presence of systemic symptoms was reported in 30% of cases, 7.4% had ECOG-PS 3–4, 71% advanced disease and 36.6% bone marrow involvement. Overall, 88% were treated with combination chemotherapy and 28% of patients with advanced stage disease in complete or partial remission after chemotherapy were consolidated with high dose therapy and stem cell transplantation. After a median follow-up of 21 months, the 2-year PFS and OS of the whole series were 38% and 52%, respectively. At the same time point, the PFS and OS (in brackets) were: PTCL-NOS (24% and 43%); AITL (40% and 50%); ENKTL (44% and 53%); ALCL ALK- (52% and 67%); ALCL ALK+ (71% and 85%) and ATLL (14% and 27%). Comparing the distribution of cases enrolled in the present study with those in the previous TCP1 (2008–2018), we found a 6% and 3% decrease in the frequency of PTCL-NOS and EATL, respectively, whilst the frequency of other histotypes remained almost unchanged. Of note, no statistically significant differences emerged in terms of PFS and OS for the comparable histotypes of TCP1 and TCP2. Conclusions: Based on the analysis of this large series of cases of PTCL prospectively registered in the TCP2, it seems “Nothing new under the sun”: no improvement in terms of outcome and a very limited effect of the WHO2016 in classification of cases in the real world. The research was funded by: Angela Serra Association for Cancer Research Keywords: Aggressive T-cell non-Hodgkin lymphoma, Pathology and Classification of Lymphomas No conflicts of interests pertinent to the abstract.

Newly diagnosed extranodal natural killer/T cell lymphoma (ENKTL) treated by anti‐PD‐1 antibody plus histone deacetylase inhibitor followed by P‐GemOx regimen

Background: ENKTL is a highly aggressive NHL with a higher incidence in Asia. In 2020 ASH meeting, we reported Sintilimab(anti-PD-1 antibody) plus Chidamide(an oral subtype-selective HDACi) yielded effective antitumor activity, durable response with mild toxicity in patients with relapsed or refractory ENKTL. We then initiated this exploratory study to investigate the efficacy and safety of Sintilimab plus Chidamide(SC) for patients with newly diagnosed ENKTL. Methods: This trial enrolled eligible patients with newly diagnosed ENKTL(ND-ENKTL); ECOG score ≤2; at least one measurable or evaluable lesion. All patients received 2–3 cycles of Sintilimab (200 mg) plus Chidamide (30 mg, twice a week). For patients with early stage, 2 cycles of SC were given, subsequent 2–4 cycles of P-GemOx regimen administered and followed by involved field radiotherapy (IFRT). For advanced stage, patients were treated with 3 cycles of SC and 3–6 cycles of P-GemOx. The primary study endpoints are the ORR of SC and end of treatment assessed according to the lymphoma response to immunomodulatory therapy criteria (LYRIC). Key secondary endpoints included DOR, PFS, OS and safety. Results: From July 2019 to Nov 2021, 42 eligible patients were enrolled from Sun Yat-sen University Cancer Center. The median age was 47.5 (range, 20–81) years, 16(38%) patients with stage III-IV, 15(31%) patients with PINK-E score≥3. All patients were evaluated for efficacy. For stage I-II, 21(81%) patients achieved response, including 18(69%) CR patients with SC. After 2 cycles of SC, 17(94%) of 18 CR patients chosen to continue SC treatment. Only 1 (6%) PR patients accepted 2 cycles of P-GemOx and got CR after chemotherapy. Twenty-five (96%) patients obtained CR after IFRT. For stage III–IV, 9(56%) patients achieved response with 13%(2/16) CR, 3(33.3%) patients experienced rapid progression disease (RPD) in SC portion. Ten (63%) patients entered P-GemOx portion including 1 RPD patient. Thirteen (81%) patient got ORR with 69% (11/16) CR after whole treatment. The median follow-up time was 24.1(5.4–44.3) months. The 2-year PFS and OS rate were 76% and 78%, the prognosis of early stage is better than advanced stage (Fig. 1). Two RPD patients died within one month. Circulating EBV-DNA clearance after SC significantly correlated with superior outcome. Forty(95.2%) patients reported treatment-related adverse effects (TRAEs). The most common TRAEs (≥10%) were neutropenia (43%), thrombocytopenia (38%), elevated transaminase (29%), and anemia (24%). The most common grade 3 TRAEs (≥10%) was elevated transaminase (10%), no grade 4 TRAEs. Keywords: aggressive T-cell non-Hodgkin lymphoma, extranodal non-Hodgkin lymphoma, immunotherapy No conflicts of interests pertinent to the abstract.

A NOVEL CONDITIONING REGIMEN OF CHIDAMIDE, CLADRIBINE, GEMCITABINE, AND BUSULFAN (CHICGB) IN THE AUTOLOGOUS STEM CELL TRANSPLANTATION OF AGGRESSIVE T‐CELL LYMPHOMA

Background: The prognosis of patients with peripheral T-cell (PTCL) or lymphoblastic T-cell lymphoma (T-LBL) remains poor under current conditioning regimens before receiving autologous stem cell transplantation (ASCT). Methods: Patients with PTCL or T-LBL were enrolled to receiviing ASCT using the conditioning regimen of chidamide, cladribine, gemcitabine and busulfan (ChiCGB). Positron emission tomography-computed tomography (PET/CT) was used to evaluate the response to ASCT. Overall survival (OS) and progression-free survival (PFS) were employed to assess patient outcome, and adverse events were used to assess the safety of the regimen. The survival curve was estimated via the Kaplan-Meier method. Results: Twenty-five PTCL and 11 T-LBL patients were recruited. The median time to white blood cell (WBC) and platelet engraftments were 10 days (8–13 days) and 13 days (9–31 days), respectively. The 3-year PFS and OS were 81.3 ± 7.2% and 88.5 ± 5.4% for all patients; 92.0 ± 5.4% and 81.2 ± 8.8% for PTCL patients; and both 81.8 ± 11.6% for T-LBL patients, respectively. The 3-year PFS and OS were both 92.9 ± 4.9% for patients with complete response (CR), but 50.0 ± 17.7% and 75.0 ± 15.3% for patients with non-CR, respectively. Infection was the most common non-hematological toxicity, and all toxicities were mild and controllable. Conclusions: ChiCGB was a potentially effective and well-tolerated conditioning regimen to improve the prognosis of patients with aggressive T-cell lymphoma. Future randomized controlled trials are needed to further assess ChiCGB as conditioning regimen for ASCT. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Chemotherapy, Stem Cell Transplant No conflicts of interests pertinent to the abstract.

LACK OF SMARCB1 EXPRESSION CHARACTERIZES A SUBSET OF PERIPHERAL T‐CELL LYMPHOMAS ENRICHED IN CHILDREN AND YOUNG ADULTS

Introduction: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Because patients respond poorly to current treatment regimens, identification of new therapeutic strategies is required. In a mouse tumor model, conditional deletion of Smarcb1 encoding a member of the SWI/SNF chromatin remodeling complex causes the majority of mice to develop mature T-cell lymphomas. The human counterpart, SMARCB1, is a bona fide tumor suppressor gene associated with the development of for example, rhabdoid tumors and schwannomas, but has also been shown to be involved in lymphocyte development. Methods: SMARCB1 (INI1) gene and protein expression was assessed in 315 patients with diverse mature T cell lymphomas by array-based mRNA profiling, immunohistochemistry and/or Western Blot. The DNA methylome was analyzed in SMARCB1-negative pediatric PTCL-NOS patients (n = 5) and murine T cell lymphomas of the Cd4-cre::Smarcb1fl/fl model (n = 5) using the Infinium MethylationEPIC and Mouse Methylation BeadChip, respectively. Murine Smarcb1-deficient T-cell lymphomas were further studied using droplet-based single cell RNA sequencing (Chromium, 10X Genomics). Results: SMARCB1 expression was heterogeneous between and within the 315 different human mature T-cell lymphoma entities. Loss of SMARCB1 expression in PTCL-NOS patients correlated with young age (Wald test, p value = 0.011). Molecular characterization and DNA methylation analysis revealed that loss of SMARCB1 expression in human PTCL largely occurs via somatic mutation and/or epigenetic silencing, whereas in contrast to rhabdoid tumors, germline SMARCB1 mutations were not observed. Comparison of the DNA methylome of human and murine PTCL-NOSSmarcb1- showed similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Increase of myeloid cell populations was confirmed in murine tumors by scRNA-seq analyses, which further revealed an immunosuppressive and pro-inflammatory tumor microenvironment (TME). Treatment of tumor-bearing mice with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversion of the exhaustion phenotype. Conclusions: Here we describe SMARCB1-negative PTCL-NOS as a potential new molecular subtype of PTCL-NOS significantly enriched in young patients. A strong concordance between naturally occurring SMARCB1-deficient PTCL in humans and in the targeted mouse model were found regarding epigenetic features. Our results provide a rationale for further investigation of potential HDACi combination therapies in SMARCB1-negative PTCL-NOS. Keywords: aggressive T-cell non-Hodgkin lymphoma, genomics, epigenomics, and other-omics No conflicts of interests pertinent to the abstract.

PTGDS PROMOTES TUMORIGENESIS OF PERIPHERAL T CELL LYMPHOMA THROUGH REGULATING IRON METABOLISM

Introduction: Accumulating evidence indicates that ferroptosis, an iron-dependent cell death, is involved in the development of tumors, and targeting ferroptosis offers great potential in tumor therapy. However, the regulatory networks of ferroptosis in peripheral T cell lymphoma (PTCL) remain unclear. Methods: Paraffin-embedded tissues of 112 PTCL patients and 38 reactive hyperplasia cases were collected with informed consents. Lentiviral vectors were stably transfected into PTCL cell lines. Tandem mass tag (TMT)-mass spectrometry and RNA-sequencing (RNA-seq) were performed for downstream analysis. Co-IP and confocal immunofluorescence were performed to verify protein–protein interaction. Xenograft models were established using SCID Beige mice. Results: Firstly, both mRNA and protein levels of PTGDS were found to be higher in PTCL cells and patients’ tissue (Figure 1A–C). Survival analysis revealed that the positive expression of PTGDS was closely associated with worse prognosis in PTCL patients (Figure 1D). PTGDS overexpression could significantly promote the proliferation of PTCL cells while PTGDS knockdown inhibited it in vitro and in vivo (Figure 2A,B). Besides, PTCL cells with PTGDS knockdown displayed a higher apoptosis rate (Figure 2C). PTGDS specific inhibitor AT56 could significantly inhibit the proliferation of PTCL cells, in a dose- and time-dependent manner (Figure 2D). Moreover, AT56 treatment induced the cell cycle arrest at G0/G1 phase in PTCL cells (Figure 2E). Analysis based on TMT-mass spectrometry found that AT56 treatment significantly regulated the expression of ferroptosis-related molecules (Figure 3A) in PTCL cells. The anti-tumor effects of sorafenib and erastin, classic ferroptosis inducers, was significantly enhanced by AT56 treatment, and Fer-1, ferroptosis inhibitor, rescued the inhibitory role of AT56 on cell proliferation (Figure 3B,C). Moreover, AT56 promoted erastin/sorafenib-induced accumulation of lipid ROS (Figure 3D), a classic biomarker of ferroptosis. Further in-vivo experiments observed that AT56 treatment enhanced the anti-tumor effects of sorafenib (Figure 3E). Mechanically, structure analysis of differentially expressed molecules in TMT-mass spectrometry identified HMOX1, a regulator of heme catabolism, as PTGDS interactive protein. Co-IP and confocal immunofluorescence assays verified their co-localization and interaction in PTCL cells (Figure 4A,B). Moreover, AT56 treatment increased the level of intracellular iron, and HMOX1 knockdown could rescue it (Figure 4C). Keywords: aggressive T-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, molecular targeted therapies The research was funded by: National Natural Science Foundation (No. 82270200, No. 82170189, No. 82070203, No. 81800194, No. 81770210); Key Research and Development Program of Shandong Province (No. 2018CXGC1213); China Postdoctoral Science Foundation (No. 2021T1404223); Translational Research Grant of NCRCH (No. 2021WWB02, No. 2020ZKMB01); Shandong Provincial Natural Science Foundation (ZR2021YQ51); Taishan Scholars Program of Shandong Province; Shandong Provincial Engineering Research Center of Lymphoma; Academic Promotion Programme of Shandong First Medical University (No. 2019QL018). No conflicts of interests pertinent to the abstract.

PILOT PHASE II STUDY OF SELINEXOR IN COMBINATION WITH IFOSFAMIDE, ETOPOSIDE AND DEXAMETHASONE IN PATIENTS WITH RELAPSED OR REFRACTORY PERIPHERAL T‐CELL LYMPHOMAS (R/R PTCLS)

Introduction: The prognosis of R/R PTCLs is very poor. Selinexor is an oral, first in class, potent selective inhibitor of nuclear exportin, that shown promising overall response rate (ORR) and complete response (CR) in a phase I study of selinexor in combination with high-dose dexamethasone, ifosfamide, carboplatin and etoposide in R/R PTCLs, Tang et al (Haematologica 2021). These results are very preliminary and need to be confirmed; for this reason, we designed the PTCL S-IDE study (EudraCT number 2021-006229-23). Methods: S-IDE is a phase II multicenter pilot study of Selinexor in combination with Ifosfamide, Etoposide and Dexamethasone in patients with R/R PTCLs. We decided to omit carboplatin in order to reduce nausea and hematologic toxicity, in addition the activity of carboplatin in PTCL is uncertain. Key inclusion criteria are: age 18–75 years, R/R histologically confirmed PTCL (PTCL-NOS, angioimmunoblastic T cell lymphoma - AITL, anaplastic large cell ALK negative—ALK neg, T-helper follicular—TFH) after at least one course of anthracycline containing regimen chemotherapy (including or not high dose chemotherapy and stem cell transplantation - SCT), PS ECOG ≤2, adequate organ function. All patients will receive intravenous S-IDE on a 21-day cycle: Selinexor (40 mg on day 3, 5 and 7); Ifosfamide 5 g/mq on day 2; Etoposide 100 mg/mq on days 1–3; Dexamethasone 20 mg/day on days 3–7. Patient in CR at the end of the 4 courses receive a maintenance with selinexor (selinexor 60 mg weekly, until progression or unacceptable toxicity) or proceed to allo-SCT or auto-SCT according to donor availability, patient age and comorbidities. The primary endpoint is ORR at the end of 4 courses of S-IDE; the secondary endpoints are duration of response, 18-months PFS and OS, treatment related mortality, CR by histotypes, rate of patients able to undergo SCT, and adverse events. Exploratory biological analyses are ORR in subgroups based on GATA3 and TBX21 expression; loss of tumor suppressor genes on the CDKN2A/B-TP3 axis and PTEN-PI3K pathways as well as genetic gains and amplification of STAT3 and MYC; the presence of mutations described as associated with a poor prognosis, including CD28 mutations in AITL; TP63 rearrangement, loss of TP53, and loss of PRDM1 in ALK− ALCL; GATA3 , TP53, and/or CDKN2A in ALK− ALCL; and alterations in histone methyltransferase genes KMT2A, KMT2B, or KDM6A and FAT1 in PTCL-NOS; XPO1 expression; circulating tumor DNA (ctDNA). The sample size is 30 patients, with enrollment 18 months in 9 Italian centers. The sample size calculation refers to the primary endpoint; a sample size of 30 patients will allow to achieve a statistical power of more than 90% (94%) to test an increase of 30% of ORR (from 50% under null hypothesis to 80% under the alternative one) using a two-sided one sample binomial test with alpha =5%. The accrual is ongoing; at the end of February 2023, 2 patients have been enrolled. Keywords: aggressive T-cell non-Hodgkin lymphoma, combination therapies, ongoing trials Conflicts of interests pertinent to the abstract. A. Chiappella Consultant or advisory role Celgene-BMS, Gilead-Sciences, Ideogen, Janssen, Roche, SecuraBIO, Takeda Other remuneration: Lecture fees/Educational activities: Astrazeneca, Celgene-BMS, Gilead-Sciences, Incyte, Janssen-Cilag, Novartis, Roche, Takeda

PRELIMINARY RESULTS OF A PHASE 2 STUDY OF CHIDAMIDE, GEMCITABINE, VINORELBINE, AND MITOXANTRONE LIPOSOME (CHI‐GVM) IN RELAPSED/REFRATORY PERIPHERAL T‐CELL LYMPHOMA

Introduction: Patients with relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) have a poor prognosis. There is no effective treatment for these patients. Mitoxantrone hydrochloride liposome showed high antitumor activity and low toxicity in lymphoma. In a phase II clinical study of mitoxantrone hydrochloride liposome monotherapy for R/R T-cell lymphoma, the overall response rate (ORR) and complete remission rate (CRR) of PTCL, not otherwise specified (PTCL, NOS) reached 34.4% and 18.8%. Our study aimed to explore whether the combination chemotherapy regimen containing mitoxantrone liposomes can improve the efficacy and survival of R/R PTCL. Methods: A Phase II, multicenter, single-arm, open-label study is planned at our center. All patients enrolled are R/R PTCL and will receive induction therapy with chidamide (20 mg, twice a week), gemcitabine (1 g/m2, d1), vinorelbine (20 mg/m2, d1), and mitoxantrone hydrochloride liposome (20 mg/m2, d1) (Chi-GVM) for 2–4 cycles. Patients aged 60 years or younger with complete remission (CR) / unconfirmed complete remission (CRu) / partial remission (PR) after 2–4 cycles of induction therapy received autologous stem cell transplantation (ASCT) prior to maintenance therapy. Patients after ASCT or patients over 60 years old with CR/CRu/PR receive maintenance therapy of chidamide (20 mg twice a week) until intolerance or disease progression (PD). Efficacy was assessed by contrast-enhanced CT or PET-CT every 2 cycles during treatment. The primary endpoint of the study was ORR and secondary endpoint was duration of remission (DOR) and1-year progression-free survival (1y-PFS). Results: A total of 7 patients were treated with Chi-GVM between September 2022 and February 2023, including 3 patients with PTCL, NOS; two patients with ALK negative anaplastic large cell lymphoma (ALCL, ALK-); and 2 patients with monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). Five male and two female were included, with a mean age of 57 years, and one patient was post-ASCT. Two patients were re-staged of stage I–II and five of stage III–IV prior to treatment, extranodal lesions including stomach, skin and intestinal. Four patients were evaluable for efficacy, 1 patient was lost to follow-up, and 2 patients did not reach the assessment time. Of the evaluable patients, 2 patients had a best response of CR and 2 patients experienced PD, one patient achieved CR and received consolidation therapy with ASCT. Grade 2 or 3 adverse events occurred in 5 patients, including 3 cases of leukopenia, 4 cases of neutropenia, 2 case of thrombocytopenia, and 1 case of hepatic insufficiency. One patient had myocardial damage before treatment, and kept stable after mitoxantrone hydrochloride liposome used. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Chemotherapy, Late Effects in Lymphoma Survivors No conflicts of interests pertinent to the abstract.

A randomized phase II trial of CHOP versus ICED and autologous stem cell transplantation in newly diagnosed T‐cell lymphoma

Purpose: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas, and their prognoses are still poor because of frequent relapses and the absence of optimal standard therapy. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the backbone of frontline chemotherapy for PTCL for many years. However, it is not clear whether anthracycline-based chemotherapies such as CHOP could be standard induction therapy for PTCL. Thus, we conducted a randomized phase II study to compare the efficacy of CHOP with fractionated ifosfamide, carboplatin, etoposide, and dexamethasone (ICED). Patients and Methods: This study was a phase II, multicenter, open-label randomized trial at 21 hospitals that belonged to the Consortium for Improving Survival of Lymphoma (CISL) in Korea (CISL-1504/ROSE study). Eligible participants were patients aged 20–65 years with previously untreated histologically confirmed PTCLs based on the World Health Organization classification 2008 including PTCL-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-negative anaplastic large-cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), and hepatosplenic T-cell lymphoma (HSTL). Patients with ALK-positive ALCL, extranodal NK/T-cell lymphoma, and mycosis fungoides/sezary syndrome were not included in the study. Patients were randomized at a 1:1 ratio to receive either CHOP or ICED every 3 weeks for 6 cycles. Upfront autologous stem cell transplantation (ASCT) was done for patients achieving complete or partial response and the primary end point was progression-free survival (PFS). Results: Between September 2015 and March 2021, 145 patients were screened, and 138 patients were enrolled. The characteristics were not different between CHOP (n = 69) and ICED (n = 66), and PTCL-NOS (n = 60) and AITL (n = 53) were dominant. The objective response rate was not different between CHOP (41/69, 59.4%) and ICED (37/66, 56.1%), and the 3-year PFS was not different between CHOP (36.7%) and ICED (33.1%, P = 0.709). Around 80% of patients who completed either CHOP or ICED followed by upfront ASCT showed 3-year overall survival (Figure 1). There was no statistically significant difference in PFS between the CHOP and ICED arms for any subgroup analyzed except AITL. CHOP was favored over ICED in AITL patients, whereas ICED was favored over CHOP in EATL/HSTL patients. ICED was associated with more anemia, neutropenia, and thrombocytopenia of all grades and grade 3 or worse, and the frequency of febrile neutropenia was higher in the ICED arm. Keywords: aggressive T-cell non-Hodgkin lymphoma, chemotherapy, stem cell transplant No conflicts of interests pertinent to the abstract.