Peripheral T-cell Lymphoma Patients Research Articles

Consolidation therapy with autologous stem cell transplantation after remission of induction chemotherapy prolongs the survival of patients with peripheral T-cell lymphoma

BackgroundThere was little evidence of autologous stem cell transplantation (ASCT) as consolidation therapy after remission of induction for patients with Peripheral T-cell lymphoma (PTCL). In this study, we conducted a comparative analysis of real-world survival outcomes between consolidation therapy and observation in patients with PTCL.MethodsA total of 92 patients with peripheral T-cell lymphoma (PTCL) who were admitted to the Department of Hematology, Huadong Hospital Affiliated with Fudan University from January 2013 to April 2019 were divided into two groups based on whether they were treated with high-dose therapy (HDT) followed by autologous hematopoietic stem cell transplantation (ASCT): ASCT as consolidation therapy (n=30) and observation (n=62). Clinical characteristics, treatment patterns, and survival outcomes were analyzed between the two groups. Univariate and Cox multivariate regression analyses were also performed to detect prognostic factors of survival.ResultsWith a median follow-up time of 41 months, the median overall survival (OS) of peripheral T-cell lymphoma patients treated with ASCT was not reached; the median progression-free survival (PFS) was 77.0 months, which was much higher than that of patients without ASCT (p<0.003 for OS, p=0.015 for PFS). Subgroup analysis found that patients with high risks benefited more from ASCT. Combination with hemophagocytic lymphohistiocytosis (HLH) (p<0.001), clinical stage more than III (p=0.014), IPI score above 3 (p=0.049), and bone marrow involvement (p=0.010) were the independent prognostic factors significantly associated with worse OS and PFS. Additionally, pegylated liposomal doxorubicin (PLD)–containing chemotherapy regimen could bring a higher overall response rate (ORR) and prolong the survival of patients with PTCL who underwent ASCT.ConclusionASCT may improve the long-term survival of patients with PTCL as consolidation therapy after achieving complete or partial remission of induction treatment, particularly for those with high risks. The chemotherapy regimen containing pegylated liposomal doxorubicin may induce deeper remission than traditional doxorubicin in PTCL. It is crucial to identify the specific groups most likely to benefit from upfront ASCT.

Brentuximab Vedotin Retreatment in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma or Peripheral T-Cell Lymphoma: A Retrospective United States Claims Analysis

Brentuximab vedotin (BV) monotherapy (BV-M) and combination (BV-C) therapies are safe and effective for classical Hodgkin lymphoma (cHL) and CD30-expressing peripheral T-cell lymphomas (PTCLs). Although the sample sizes have been small (12–29 patients), in clinical studies, response rates of 53–88% have been reported for BV retreatment in patients with an initial BV response. We evaluated the real-world characteristics and treatment patterns of cHL/PTCL patients who received BV and were retreated in the United States. Symphony Health Patient Claims (11/2013–1/2022) were retrospectively analyzed to identify cHL/PTCL patients treated with BV and retreated with BV-M, BV-C, or non-BV therapy. Patient characteristics were described by retreatment, and predictors of BV-M retreatment were identified. Among the cHL and PTCL patients treated with BV (n = 6442 and 2472, respectively), 13% and 12%, respectively, were retreated with BV; the median times from initial BV to BV-M retreatment were 5 and 7 months, respectively; and the numbers of BV-M retreatment doses were 4 and 5, respectively. Among cHL patients, the predictors of BV-M retreatment were age (18–39 vs. ≥60 years), sex (women vs. men), and previous stem cell transplantation (yes vs. no). Among PTCL patients, the only predictor of BV-M retreatment was systemic anaplastic large-cell lymphoma subtype (yes vs. no). Real-world data support clinical study results suggesting earlier BV treatment be considered, as BV retreatment may be an option.

Role of plasma EBV-DNA load and EBER status on newly diagnosed peripheral T-cell lymphoma.

To explore the prognostic and therapeutic role of Epstein-Barr Virus (EBV) on peripheral T-cell lymphoma (PTCL). Totally 262 newly diagnosed PTCL patients who were hospitalized from January 2014 to December 2022 were retrospectively enrolled. Molecular analysis included 31 eligible patients. EBV-encoded RNA (EBER) presence in tumor tissue and EBV DNA levels in patients at baseline (DNA1) and after 4 cycles of chemotherapy (DNA4) were assessed. Our findings revealed that the EBER-positive cohort exhibited significant differences compared to counterparts in overall survival (OS, P = 0.047) and progression-free survival (PFS, P = 0.009). Both DNA1 and DNA4 were significantly associated with inferior OS. Multivariate analysis demonstrated that DNA4 independently affected PTCL prognosis for OS (hazard ratio = 5.1617; 95% confidence interval 1.1017-24.1831; P = 0.037). Treatment with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus azacytidine regimen showed a better OS compared to CHOP or CHOP plus etoposide for patients with partially positive EBER and EBER positive statuses (P = 0.192), although the improvement was not statistically significant. This study delineated the genetic paradigm of PTCL, comparing genetic differences by EBV status and found that EBER partially positive plus positive patients were more likely to have DNMT3A (P = 0.002), RHOAG17V (P = 0.023), and TET2 mutations (P = 0.032). EBER, DNA1, and DNA4 emerged as sensitive markers for prognosis. CHOP plus azacytidine might present a preferable option for PTCL patients with DNA methylation due to EBV infection.

Abstract 2737: LIS22, a first in class polyclonal antibody immunotherapy in T cell blood cancers

Abstract Background: Several approaches such as antibody drug conjugate (ADC), chimeric antigen receptor T cells (CAR-T) and recently bispecific antibodies are being introduced as innovative weapon in B-Cell lymphoma treatment. In the opposite, very limited therapeutic options are available for the treatment of rare refractory T cell malignancies such as PTCL. The 5-year survival rate of PTCL is lower than 30% according to the recent clinical data. Developing new effective treatment strategies for PTCL is an urgent problem. LIS22, is a first in class glyco-humanized polyclonal antibody (GH-pAb), targeting multiple tumor-associated antigens simultaneously. In this study, we characterized the safety and efficacy of LIS22 in preclinical models of T cell malignancies. Material and Methods: LIS22 ability to induce Antibody-Dependent Cell Cytotoxicity (ADCC), Antibody-Dependent Cellular Phagocytosis (ADCP), Complement Dependent Cytotoxicity (CDC), and apoptosis was tested in a panel of hematologic malignancy cell lines and peripheral blood mononuclear cell (PBMC). To assess the targeting and recognition of LIS22 in PTCL patients, we evaluated the immunolabelling of LIS22 on patients’ biopsies (n=119) using tissue microarray. LIS22 efficacy in vivo were evaluated in NMRI nude mice and SRG rats using T1301 and Jurkat cancer cell lines. Pharmacokinetics and safety of this drug were assessed in cynomolgus monkeys after single and repeated IV dosing up to 50mg/kg. Results: LIS22 acts via several mechanisms, at 30µg/ml, it induced cytotoxicity via CDC (in 70%), ADCP (in 49%), ADCC (in 41%) and apoptosis (in 30%) of HPB-ALL human T blood cancer cell line but not in PBMC. LIS22 showed a potent in vitro antitumor activity in a panel of hematologic malignancy cell lines, it induced specific tumor cell CDC (EC50=41.4±28.9µg/mL). In both CDC and apoptosis cytotoxicity assays, LIS22 displayed a significantly higher potency on T cell blood cancers and no toxicity on healthy blood cells compared to PTCL clinically active drug Alemtuzumab (Anti-CD52). It was able to kill up to 100% of the cancer cells without affecting PBMC. In immunolabeling assay, LIS22 demonstrated cross-reaction to PTCL patient biopsy (staining up to 93%). In vivo efficacy studies in different mice and rat xenograft models, LIS22 induced a significant reduction of tumor growth up to 90% across several tested tumors. LIS22 was also characterized by high tolerance profile and satisfactory exposure in monkeys after repeated dosing (up to 250mg/kg of cumulative dose). Conclusion: LIS22 appeared as a novel and promising cancer immunotherapy against T Cell hematologic malignancies. It has already been administered to human in another indication and showed a satisfactory PK and safety profile (no signs of immunotoxicity or systemic cytokine release). LIS22 is now ready to enter Phase I/II in the coming months for the treatment of peripheral T cell lymphoma (PTCL). Citation Format: Carine Ciron, Francoise Shneiker, Ophélie Dauphouy, Juliette Rousse, Pierre-Joseph Royer, Gwenaelle Evanno, Odile Duvaux, Firas Bassissi. LIS22, a first in class polyclonal antibody immunotherapy in T cell blood cancers [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 2737.

Pre-treatment [18F]FDG PET/CT for assessing bone marrow involvement and prognosis in patients with newly diagnosed peripheral T-cell lymphoma

ABSTRACT Purpose To explore the value of [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in assessing bone marrow involvement (BMI) and prognosis in newly diagnosed peripheral T-cell lymphomas (PTCLs) before treatment. Methods This retrospective study included 201 eligible PTCLs who received pre-bone marrow biopsy (BMB) and PET/CT. The status of bone marrow (BM) by PET was assessed using a visual examination and a quantitative index (the maximal standardized uptake value [SUVmax] of BM divided by the SUVmax of the liver [M/L]). Results Totally 148 patients had no evidence of BMI by PET or BMB; BMI was detected by both methods in 16 patients. The sensitivity and specificity of PET/CT for patients with confirmed BMI by BMB were 43.2% and 90.2%, respectively (κ =  0.353). In addition, 25 patients assessed by PET/CT staging (having stage I to II disease) had no evidence of BMI detected by both PET/CT and BMB. Image-guided biopsy was also recommended when PET/CT showed a focal FDG uptake outside the iliac crest. Survival analysis revealed that BMB was significant for overall survival (OS) (P = 0.020) while M/L for both progression free survival (P = 0.002) and OS (P < 0.001). In multivariate analysis, M/L (HR 1.825, 95% CI 1.071-3.110, P = 0.027) was an independent prognostic factor for OS. There were no statistical differences at the genetic level about BMI confirmed by PET or BMB. Conclusion PET/CT has a complementary role in assessing BMI and an ability to predict prognosis in PTCL patients.

Role of upfront autologous transplant for peripheral T-cell lymphoma patients achieving a complete remission with first-line therapy: a systematic review and meta-analysis.

There is currently no consensus on the role of upfront autologous transplantation (ASCT) for patients with peripheral T-cell lymphomas (PTCL), especially in patients achieving first complete remission (CR1) following chemotherapy, and data in the literature is conflicting. A systematic review and meta-analysis was performed to address this question. We searched key databases from January 2000 to February 2022. Six prospective and eleven retrospective studies were included among 2959 unique records. Median follow up in these studies ranged from 22 to 94 months. There was a trend towards benefit in PFS (HR = 0.80, 95% CI 0.62-1.05, p = 0.11) and OS (HR = 0.79, 95% CI 0.57-1.09, p = 0.15) in the ASCT compared to chemotherapy only group. Importantly, in transplant eligible patients in CR1, a significant benefit was demonstrated in both OS (HR = 0.59, 95% CI 0.36-0.95, p = 0.03) and PFS (HR = 0.61, 95% CI 0.47-0.81, p = 0.0004) in the ASCT group. Amongst the nodal PTCL subgroups, ASCT showed a significant PFS benefit for the AITL subgroup (HR = 0.43, 95% CI 0.20-0.94, p < 0.03) but not PTCL-NOS or ALK-ve ALCL subgroups. Our findings support upfront ASCT for transplant eligible PTCL patients achieving CR1 post chemotherapy. In particular, patients with AITL exhibited a significantly better PFS after upfront ASCT.

18F-FDG-PET/CT response after first-line treatment as a prognostic factor for survival in peripheral T-cell lymphoma: a Spanish retrospective study

ABSTRACT Background An accurate assessment of tumor viability after first-line treatment is critical for predicting treatment failure in peripheral T-cell lymphomas (PTCLs). 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) has been adopted as the preferred assessment method in clinical trials, but its impact in clinical practice should be examined. This study aims to determine the prognostic significance of18F-FDG-PET/CT for survival following first-line treatment in PTCL patients. Research design and methods Retrospective observational study including 175 patients diagnosed with PTCL between 2008 and 2013 in 13 Spanish sites. Results Fifty patients were evaluated with18F-FDG-PET/CT following first-line therapy: 58% were18F-FDG-PET/CT-negative and 42% were18F-FDG-PET/CT-positive. Disease progression occurred in 37.9% of18F-FDG-PET/CT-negative patients and in 80.9% of18F-FDG-PET/CT-positive patients (p = 0.0037). Median progression-free survival and overall survival were 67 and 74 months for18F-FDG-PET/CT-negative patients, and 5 (p < 0.0001) and 10 months (p < 0.0001), respectively, in18F-FDG-PET/CT-positive patients. After multivariate analysis, only B symptoms emerged as a negative predictive factor of complete response (RR 7.08; 95% CI 1.60–31.31; p = 0.001). Conclusions 18F-FDG-PET/CT identifies high-risk PTCL patients who will have poor prognosis and survival following first-line treatment. However, more research is needed to confirm the best treatment options for PTCL patients.

NOT OTHERWISE SPECIFIED T-CELL LYMPHOMA: OUTCOMES OF A SINGLE CENTER STUDY.

The peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is the most common subtype of peripheral T-cell lymphoma (PTCL). It constitutes approximately 25% of all PTCLs and accounts for more than 15% of all lymphomas. The results of the first Ukrainian prospective study of patients with PTCL-NOS are presented in the article. The aim of the study was to analyze the morbidity of PTCL patients and the treatment performed, to evaluate overall survival and progression-free survival, and to determine the factors that predict the treatment response. An analysis was performed on the data of 31 patients diagnosed with peripheral PTCL-NOS from February 2018 to the present. T-cell lymphoid neoplasms were diagnosed according to the 2016 WHO classification. The treatment regimens were in alignment with ESMO and NCCN guidelines. More than 90% of patients were prescribed anthracycline-based regimens (CHOP; CHOEP - cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone). An initial treatment was performed with CHOP-based regimens in 38.70% (n = 12) of patients, with the addition of etoposide in 58.06% of patients (n = 18). The response was assessed according to the response criteria for malignant lymphoma (Cheson, 2008, 2014). The overall response to therapy was 58.06% (n = 18), with complete responses in 29.03% of patients and partial responses in 29.03% of patients. The stabilization of the disease occurred in 3.44%, while the disease progression in 41.37% of patients. The 12-month and 24-month survival rates were 75.44% and 50.81%, respectively. The 12-month and 24-month progression-free survivals were 47.68% and 33.1%, respectively. Ki-67 overexpression (> 65%) was a negative prognostic factor. The results of the treatment of PTCL obtained in a Ukrainian population study are similar to those in other European studies, all of which remain unsatisfactory. Further research is required to develop a new strategy for examination and therapy to improve treatment outcomes. The emphasis should be placed on the pragmatic clinical trials comparing the efficacy of first-line treatment in PTCL patients with both favorable and unfavorable clinical factors.

Up-front autologous stem cell transplant in peripheral T-cell lymphoma patients achieving complete response after first-line treatment: A multicentre real-world analysis.

We conducted a retrospective, multicentre study to compare consolidation therapy with or without first-line autologous stem cell transplant (ASCT) for peripheral T-cell lymphoma (PTCL) patients in a real-world setting. We enrolled 347 PTCL patients who achieved complete response after first-line treatment. Of these, 257 received consolidation chemotherapy (non-ASCT group) and 90 received ASCT (ASCT group). Clinical outcomes were comparable between ASCT and non-ASCT groups. After propensity score matching, the 2-year cumulative incidence of treatment-related mortality and relapse remained similar between groups (1.9% vs. 2.0%, p = 0.985; 24.7% vs. 47.1%, p = 0.021). However, significant differences emerged in progression-free survival and overall survival probabilities. Within the T-cell lymphoma subgroup, ASCT patients exhibited favourable outcomes compared to non-ASCT patients: 2-year progression-free survival (73.4% vs. 50.8%, p = 0.024) and overall survival (92.1% vs. 73.5%, p = 0.021). Notably, no significant differences were observed for patients with NK/T-cell lymphoma. These real-world data suggest that up-front ASCT is a safe and effective consolidation option for PTCL patients in remission, particularly those with T-cell lymphoma.

Prognostic impact of pretreatment cell-free DNA concentration in newly diagnosed peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) have a poor prognosis and, to date, there are no reliable predictive biomarkers of response. In this work we explored the prognostic impact of cell-free DNA (cfDNA) concentration in 75 newly diagnosed patients enrolled in a prospective multicenter study. Pre-treatment cfDNA was strongly associated with clinical risk factors and was identified as a superior predictor for shorter progression-free survival in multivariable analysis, outweighing canonical risk parameters. Furthermore, we identified a cfDNA value above which survival worsens. In conclusion, pre-treatment cfDNA concentration represents an easily usable predictive biomarker that is highly associated with survival of PTCL patients.

Epigenetic Priming By Hypomethylation Enhances the Immunogenic Potential of Tolinapant in T-Cell Lymphoma

Background:Durable single-agent responses with the IAP antagonist, tolinapant (ASTX660), have been reported in peripheral T-cell lymphoma (PTCL) and cutaneous TCL (CTCL) patients (NCT02503423, Michot et al., EHA 2022). We have found that tolinapant has the potential to drive immunogenic form of cell death (ICD), such as necroptosis, in preclinical models of TCL (Ferrari et al., Blood Adv. 2021). Here, we further explored this by modulating key necrosome components in TCL cell lines and analysing changes in cell death signalling. We hypothesised the epigenetic mechanisms that limit induction of ICD could be reversed by combining tolinapant and hypomethylating agents, such as decitabine. Our biomarker-led approach demonstrated that this novel combination could overcome inherent resistance to a form of cell death that can engage a strong immune response. Materials and Methods: Key necrosome components were modified in human and mouse TCL cell lines by CRISPR knockout and activation, and effects of tolinapant on their viability measured in vitro. Promoter methylation was assessed by pyrosequencing following bisulfite treatment (EpigenDx). Effects of tolinapant and decitabine, as single-agents and in combination, on cytokine/chemokine release were assessed using Meso Scale Discovery (MSD) or Luminex assay. ICD biomarkers in cells and tumor lysates were analysed by ELISAs, MSD assays, qPCR and Western blotting. In vivo activity of tolinapant and decitabine were tested in caspase-8 knockout EL4 cells in a syngeneic setting. PTCL patient plasma samples were analysed by Human ExplorerMAP™ v. 1.0 (Luminex xMAP® technology). Results: Loss of necrosome components or necrosome inactivation led to reduced sensitivity of TCL cells to tolinapant. We confirmed decitabine treatment resulted in re-expression of necrosome proteins (e.g., RIPK3) and cancer testis antigens. Combination of decitabine and tolinapant led to increased lytic cell death over monotherapies, and this was accompanied by increased levels of interferon signalling and ICD biomarkers (e.g., HMGB1). Tolinapant treatment alone, or in combination with decitabine, led to elevated chemokine release from dying TCL cells. These observations indicate activation of necroptosis. In vivo, the combination treatment prolonged survival of mice bearing caspase-8 knockout EL4 tumors while monotherapies had limited effects. We also report that IP-10 (CXCL10) levels were increased in plasma samples of tolinapant-treated PTCL patients, as well as other plasma proteins, implying immune activation. Conclusions: We demonstrate that tolinapant acts as an immune modulator via promoting ICD, and this can be enhanced by epigenetic reprogramming with decitabine. These findings provide a rationale to support the on-going combination study of tolinapant with ASTX727 (oral decitabine and cedazuridine) that recently started in PTCL (ASCERTAIN-P, NCT05403450). It has also identified putative biomarkers of immunomodulatory activity that could be utilized in clinic.

Impact of Front-Line Treatment Interim PET/CT in Peripheral T-Cell Lymphoma Patients' Survival: Experience of a Single Center

Introduction: The introduction of PET/CT in the staging and response assessment to therapy has changed the clinical evaluation of most lymphomas, especially Hodgkin lymphoma and aggressive B-cell lymphomas. The use of PET/CT in the staging of peripheral T-cell lymphomas (PTCL) is already a standard of care in many centers, although its decisional role in course of chemotherapy or at the end of treatment remains unclear. Objective: The aim of this study is to evaluate the predictive role of interim PET/CT in newly diagnosed PTCL patients. Methods: We retrospectively analyzed the clinical data of adult patients diagnosed with PTCL and actively treated between 2014 and 2023 at our center. All patients were evaluated with PET/CT at different timepoints (baseline, interim and end of treatment). Results: We evaluated 49 patients, with a median age at diagnosis of 59 years (range: 18-83), and a slight predominance of females (54%) (table 1). Almost half of the patients were diagnosed of angioimmunoblastic/T-follicular helper lymphoma (AITL/TFHL) 23(47%), followed by anaplastic large cell lymphoma (ALCL) in 17 cases [9 ALK+ (18%) and 8 ALK- (17%))] and peripheral T-cell lymphoma NOS (PTCL-NOS) in 9 (18%). Seven (14%) patients had ECOG ≥ 2, 47 (90%) had stage III-IV disease, among them, 42 (84%) with extranodal involvement. Bone marrow was involved in 14 out of 36 (39%) evaluated patients. Twenty-seven (54%) patients had IPI score 3-5. Front-line treatment consisted in CHOP in 32 (65%) patients and brentuximab vedotin+CHP in 17 (35%). Interim evaluation was performed after 3 cycles in 32 (65%) and after 4 cycles in 16 (33%) patients. Only one patient was evaluated after 2 cycles due to suspected disease progression. At this time point, 31 (63%) patients were considered in complete metabolic response (CMR) with a Deauville Score (DS) 1-3, 12 (25%) in partial metabolic response (PMR) with a DS 4 and 6 (12%) patients with progressive disease (PD) with DS5. Among the latter's, 4 patients were treated with 2 nd line treatment, while 2 completed the planed 6 cycles due to significant tumor burden . Among 48 patients evaluated after 3 and 4 cycles of therapy, CMR was achieved in 18 (56%) and 13 (81%), respectively (p=0,088). Eleven (34%) and one (6%) pts were in PMR at iPET after 3 and 4 cycles, respectively. Forty-five (92%) patients completed front-line therapy and were evaluated with EOT PET/. CMR (DS1-3) was reported in 32 (71%) patients, PMR in 8 (18%) and PD in 5 (%). Among patients with CMR at iPET, 25 (81%) maintained CMR, 5 (16%) converted to PMR and only 1 (3%) progressed. Among patients with PMR at iPET, 5 (42%) converted to CMR, 4 (33%) maintained PMR and 3 (25%) progressed. Eighteen (37%) patients were consolidated with autologous stem cell transplantation, all in CMR at EOT, except for 1 patient with PMR DS4. With a median follow-up of 28 months (range: 2-107 months), 25 (51%) patients relapsed or progressed. Median progression-free survival (PFS) of the entire population was 24 months. According to interim response, median PFS of DS1-3, DS4 and DS5 were 28, 10 and 2 months, respectively (Figure 1). In univariate analysis, along traditional prognostic factors as advance stage (p=0.0324), increased LDH (0.0211), IPI ≥ 3 (0.0198) and bone marrow infiltration (0.0475), interim PET/CT (iPET) impacted on PFS (DS1-3 vs DS4 vs DS5, p=0.004; DS1-3 vs DS4-5, p=0.0233). When considering the exact timing, iPET after 4 cycles seemed to relate better with PFS (DS1-3 vs DS4 vs DS5, p=0.0009) than after 3 cycles (DS1-3 vs DS4 vs DS5, p=0.32). In the multivariate analysis, iPET/CT response maintained its prognostic significance (for DS1-3 vs DS4 vs DS5: HR 2.37, 95% CI 1,44-3,89, p=0,). Median OS was not reached. The estimated 2-year OS for the entire population was 75% (95% CI, 58-86). According to iPET, the estimated 2-year OS for DS1-3, DS4 and DS5 were 85% (60-95), 64% (30-85) and 63% (14-90), respectively. No impact of iPET was documented on . Conclusion: Our study highlights the potential role of interim PET/CT in the management of PTCL. Reaching an early metabolic complete remission seems to be associated with longer PFS. Patients with a DS4 at interim evaluation remain challenging for clinicians, since also in our study half of them converted to CMR at the end of . Further radiomics analysis may help to better identify patients at higher risk of progression and offer a more tailored treatment.

A Multicenter, Open-Label, Single-Arm, Phase Ib Clinical Trial of HH2853 in the Treatment of Patients with Relapsed and/or Refractory Peripheral T-Cell Lymphoma

Introduction Peripheral T cell lymphoma (PTCL) is an aggressive tumor type with poor survival, whereas treatment options for relapsed and/or refractory (r/r) disease are very limited. Standard treatments have a median progression free survival (PFS) of only 3-4 months. HH2853, the novel, potent and selective dual inhibitor of Enhancer of Zeste Homolog 1 and 2 (EZH1/2), has demonstrated a clinical benefit with a favorable safety profile in Phase 1 and Phase 2 trials in solid tumors and R/R non-Hodgkin's lymphoma (NHL) previously. Here we report the efficacy and safety data from phase 1b trial of HH2853 in r/r PTCL. Methods The Phase 1b clinical trial in PTCL (CTR20221416) was conducted from July, 2022 to June 15, 2023 at 15 sites in China. This study consisted of two parts. In part 1, 3+3 dose-escalation design with three dose levels of HH2853 (300mg, 400mg, 600mg BID) was used to identify the MTD and recommended Phase II dosage (RP2D) of HH2853. Part 2 was dose expansion at two dose groups (300mg and 400mg BID). HH2853 was orally dosed until disease progression, intolerable toxicity or withdrawal from the study. Safety was evaluated according to CTCAE v5.0. Tumor assessments were performed according to LUGANO 2014 every 2 treatment cycles (28-day/cycle). A final data cut off (DCO) on June 15, 2023 was conducted for safety and efficacy assessments. To that date, there were still 25 pts (73.5%) remained on HH2853 treatment. Results In this study in r/r PTCL, 34 pts enrolled with different PTCL histology types, including AITL (14 pts, 41.2%), PTCL-NOS (11 pts, 32.4%), ALK -ALCL (4 pts,11.8%), NKT (2 pts, 5.9%), TFH (2 pts, 5.9%), SKIN-PTCL (1 pt, 2.9%). Pts were a median age of 58 years (range: 34 to 79), ECOG 0-1 (ECOG 0, 9 pts, 26.5%, ECOG 1, 25 pts, 73.5%), had a median of 2 lines (range 1 to 5) prior systemic therapies, 6 pts (17.6%) had bone marrow involvement at the baseline. With 30 pts (88.2%) having prior CHOP or CHOP-like therapy，with 14 pts (41.2%) were refractory to their last treatment. 1pts (2.9%) had undergone hematopoietic stem cell transplantation. 32 patients (92.1%) had experienced a treatment related adverse event (TRAE), 7 pts (20.6%) experienced grade ≥3 TRAE. The most common TRAEs (≥10%) were PLT decreased (14 pts, 41.2%) , anaemia (13 pts, 38.2%)，and diarrhoea (11 pts, 32.4%). The frequently reported TRAEs of grade ≥3 with an incidence of ≥10% were PLT decreased (5 pts, 14.7%) and neutrophil count decreased (4 pts, 11.8%). 8 pts (23.5%) had dose interrupted due to TRAE. 3 pts (8.8%) had dose reductions due to TRAE from 600 to 400 mg BID, 1 pts (6.3%) had dose reductions from 400 to 200 mg BID, and 1 pts (2.9%) discontinued from the study due to TRAEs. The safety profile was consistent to that had been observed in HH2853 studies. 1 pt (2.9%) at 600mg BID experienced dose limiting toxicity (DLT)due to grade 4 PLT decreased. The majority of TRAEs were reversible or clinically manageable. Among the 34 enrolled pts, 28 patients had the evaluated response, the Overall Response Rate (ORR) was 60.7% (17 pts), including 21.4% (6 pts) Complete Responses (CR), 39.3% (11 pts) Partial Responses (PR) and 14.3% (4 pts) Stable Disease (SD), contributing to an 75.0% (21 pts) Disease Control Rate (DCR). The median time to response (mTTR) was 1.87 months (95% CI: 1.77, 2.17). At DCO the median follow up of the pts in the study was 2.79 month (IQR: 1.94, 5.88). The median Duration of Response (mDOR), the median Progression Free Survival (mPFS) and the median OS (mOS) had not reached. The 3-month PFS rate was 74.44% (95%CI:53.62%,86.95%). The 6-month OS rates was 91.97% (95%CI: 71.50%, 97.93%). Conclusions The selective EZH1/2 dual inhibitor HH2853 demonstrated good safety and promising efficacy in r/r PTCL patients, indicating its potential as a therapeutic option for this difficult to treat patient population.

Phase 2 Study of Golidocitinib, a JAK1 Selective Inhibitor, As Maintenance Therapy in Patients with Peripheral T Cell Lymphomas after First-Line Systemic Therapy (JACKPOT26)

Introduction: Peripheral T cell lymphomas (PTCLs) are a group of rare non-Hodgkin's lymphomas. The first-line standard therapy is CHOP or CHOP-like regimens, and ~50-65% patients could achieve tumor response. However, approximately 40% of patients with complete response and 80% of patients with partial response had disease relapse within 2 years after initial tumor response, and the prognosis of relapsed patients was very poor. There is a lack of standard maintenance therapy for this group of patients. Golidocitinib is a JAK1 selective inhibitor which showed promising antitumor efficacy in patients with relapsed or refractory PTCLs. Here we report the antitumor efficacy and safety of golidocitinib as maintenance treatment after first-line therapy in a phase 2 clinical trial (JACKPOT26, CTR20213318). Methods: PTCL patients who achieved tumor response post first-line therapy were enrolled and received golidocitinib treatment at 150 mg once daily (QD). This study included two cohorts: cohort 1 (complete response post first-line therapy) and cohort 2 (partial response post first-line therapy). The objectives were to assess safety and antitumor efficacy of golidocitinib as maintenance therapy. The efficacy endpoints included the rate of patients who were 1-year and 2-year disease free survival (DFS) for cohort 1, and progression free survival (PFS), objective response rate (ORR), duration of response (DoR) for cohort 2, respectively. Tumor response was assessed by investigators based on CT images per Lugano 2014 criteria. Endpoints for safety assessments are treatment emergent adverse events (TEAEs) and serious adverse events (SAEs), etc. Results: A total of 48 patients with PTCL who had achieved tumor response post first-line treatment were enrolled, including 30 patients with complete response (cohort 1) and 18 patients with partial response (cohort 2). The median age was 58.5 years (range: 25 to 74), and 52.1% were male. Major pathological subtypes included: AITL (31.3%), NOS (27.1%) and NK/TCL (27.1%). All dosed patients were included in the efficacy and safety analysis. As of June 27, 2023, the median duration on treatment for all patients was 7.1 months. In cohort 1, with median follow-up time of 8.1 months, median DFS has not been reached, with 86.7% patients still responding. In nodal subtypes（AITL, NOS, ALK-ALCL）, with median follow-up time of 8.3 months, median DFS has not been reached, with 82.4% patients still responding. In cohort 2, with median follow-up time of 5.6 months, median PFS has not been reached, with 66.7% patients still responding. The ORR of cohort 2 was 38.9%, and complete response rate (CRR) was 33.3%. In 10 patients with measurable disease at the baseline, six patients (60%) achieved tumor response, with 5 patients achieved complete response. With medina follow-up time of 3.7 months, the median DoR has not been reached, with 85.7% of patients still responding. The estimated 6-month and 9-month DoR rates were 100% and 100%, respectively. The safety profile of golidocitinib was similar as what has been reported previously. A total of 32 patients (66.7%) reported ≥ grade 3 drug-related TEAEs. The most common ≥ grade 3 drug-related TEAEs were hematological adverse events in nature, including neutropenia (37.5%), leukopenia (31.3%), lymphopenia (10.4%) and thrombocytopenia (6.3%). The majority of these TEAEs were reversible and clinically manageable. Only one patient discontinued golidocitinib treatment due to drug-related TEAEs. No drug-related TEAEs leading to fatal outcome was reported. Conclusions: In conclusion, golodocitinib showed manageable safety profile and promising effect in maintaining and enhancing tumor response in patients with PTCL post first-line therapies. This result supports further clinical development of golidocitnib in the first-line setting. The updated data will be presented in the conference.

A Retrospective Study on the Efficacy and Safety of Chidamide As a Maintenance Therapy for Peripheral T-Cell Lymphoma

Background: Peripheral T-cell lymphomas (PTCLs) are a set of rare and highly heterogeneous tumors of non-Hodgkin's lymphoma (NHL) with inferior outcomes. Chidamide is a novel benzamide class of histone deacetylase (HDAC) inhibitor (HDACi) that was approved by the Chinese Food and Drug Administration in 2014 for the treatment of relapsed or refractory (R/R) PTCL patients. This study aimed to assess the efficacy and safety of chidamide as a maintenance therapy after induction or salvage treatment in patients with PTCLs. Methods: The clinical data of 58 patients with different PTCL subtypes who received chidamide as a maintenance therapy after first-line or salvage treatment were collected. Progression-free survival (PFS), overall survival (OS), and safety were analyzed. Results: Fifty-eight patients enrolled in our study between January 2015 and July 2022, of whom 39 patients received chidamide as a maintenance therapy after first-line treatment and 19 patients after salvage treatment. All patients started chidamide maintenance after reaching at least partial response (PR). The median age was 66 (29-83) years. Patients with angioimmunoblastic T-cell lymphoma (AITL) represented the largest subgroup (34, 58.6%), followed by PTCL, not otherwise specified (PTCL-NOS) (10, 17.2%), anaplastic large cell lymphoma (ALCL) (8, 13.8%), NK/T cell lymphoma (NKTCL) (5, 8.6%) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) (1, 1.7%). Thirty-four (58.6%) patients were stage III-IV, and 38 (65.5%) patients had intermediate or high risk (prognostic index for T-cell lymphoma (PIT) 2-4). Among the 39 patients who underwent chidamide maintenance after first-line treatment, 30/39 (76.9%) patients began maintenance after reaching complete response (CR) and 9/39 (23.1%) after achieving PR. Notably, 8/9 (88.9%) patients achieved CR from PR during maintenance treatment, with a median time of 6 (3-12) months. A total of 11/39 (28.2%) patients experienced disease progression during the maintenance treatment, and their median duration of remission was 6 (3-13) months. Among them, 2 patients experienced disease progression 2 to 3 months after drug withdrawal due to COVID-19 infection. A total of 19 patients who received maintenance treatment after salvage therapy, 9 (47.4%) received maintenance therapy after CR and 10 (52.6%) received maintenance therapy after PR. Among them, 9/19 (47.4%)had disease progression and their median duration of remission was 16 (2-25) months. The remaining 10 patients (8 CR and 2 PR) were still undergoing maintenance treatment and follow-up. The median maintenance treatment time for all patients was 16 (1-72) months, and the median maintenance dose was 20 (15-30) mg twice weekly. The median follow-up time was 39 (2-79) months, the median PFS was 33 months, and the median OS had not been reached (Figure 1 a, b) for all patients. The median PFS and OS of the patients who received first-line maintenance therapy were not reached, which were significantly better compared to patients who received chidamide as salvage treatment maintenance (the median PFS and OS were 7 and 67 months, P &amp;lt; 0.001, P = 0.009, respectively) (Figure 1 c, d). There was no statistical difference in PFS and OS among the different pathological subtypes, but AITL seemed to achieve better PFS (Figure 1 e, f). The most common toxicities were hematologic toxicities, including neutropenia (42, 72.4%), anemia (23, 39.7%), and thrombocytopenia (29, 50.0%), followed by fatigue (35, 60.3%), anorexia (31, 53.4%), liver dysfunction (10, 17.2%), and pneumonia (4, 6.9%). Most adverse events were grade 1 or 2, and the grade 3‒4 adverse events were neutropenia (15/42), thrombocytopenia (7/29), fatigue (1/35), and pneumonia (2/4). Twelve (20.7%) patients underwent a dose reduction and three patients discontinued treatment (two patients with severe pulmonary infections, and one patient had intolerable fatigue) due to adverse events. One patient stopped maintenance treatment after taking chidamide for 10 months for financial reasons and he is still in follow-up. Conclusion: The findings of this study showed that patients with chidamide maintenance therapy had a better PFS and OS with a manageable safety profile, especially as the first-line maintenance therapy. We conclude that chidamide can be used as a maintenance treatment to improve the survival of patients with PTCLs.

Strategies to Develop Anti-KIR Mab Lacutamab in Patients with Peripheral T-Cell Lymphoma: Preliminary Monotherapy Clinical Data and Pre-Clinical Combinability Data

Peripheral T-cell Lymphoma (PTCL) is a heterogeneous group of aggressive T-cell lymphomas associated with poor prognosis. Many patients with PTCL do not respond or relapse despite responding to first line systemic therapy. Despite the common use of chemotherapies, there is no universally accepted standard of care. This highlights an urgent and significant need for innovative treatment strategies that incorporate novel mechanisms of action, particularly for patients with relapsed or refractory (R/R) PTCL. One such novel target is KIR3DL2, a killer immunoglobulin-like receptor that is expressed across different subtypes of T-cell lymphomas including approximately 50% of PTCL patients. Lacutamab is a first-in-class monoclonal antibody designed to specifically deplete KIR3DL2-expressing cells through antibody-dependent cell-cytotoxicity (ADCC) and antibody-dependent cell-phagocytosis (ADCP). It is being developed as a novel treatment for patients with R/R PTCL as a single agent or in combination. In previous trials in patients with R/R cutaneous T-cell lymphoma (CTCL), lacutamab showed acceptable safety profile with no dose limiting toxicities and promising activity. Here we provide preclinical combination data supporting anti-tumor activity and rationale for the exploration of lacutamab in combination with approved and novel therapies in patients with PTCL and we present preliminary monotherapy data from an ongoing Phase 1b study in PTCL. To further develop novel-lacutamab combinations, the combinability of lacutamab with therapies used in R/R or frontline PTCL e.g., pralatrexate or CHOP, respectively, was tested. Pralatrexate is an antineoplastic folate analog approved for the treatment of R/R PTCL. In vitro, pralatrexate was shown to induce KIR3DL2 upregulation on several tumor cell lines with endogenous or forced KIR3DL2 expression and to enhance lacutamab-induced ADCC by NK cells. Importantly, the combination of lacutamab with pralatrexate in vivo delayed tumor growth (Figure 1A) and improved survival (Figure 1B) compared to each monotherapy. CHOP-based chemotherapy is a standard of care in the frontline treatment of PTCL subtypes. In a preclinical in vivo human tumor model, lacutamab in combination with CHOP was shown to reduce tumor growth compared with CHOP or lacutamab alone. An ongoing multi-center, open-label, Phase Ib trial (NCT05321147) evaluate the safety and efficacy of lacutamab monotherapy in patients with KIR3DL2-expressing R/R PTCL who have received at least one prior line of systemic therapy. Lacutamab 750 mg is administered as an intravenous infusion weekly x 5 weeks, every 2 weeks x 10 then every 4 weeks until disease progression or unacceptable toxicity. The primary objective was to assess the safety and tolerability of lacutamab in R/R PTCL. Secondary objectives were to assess clinical activity and to characterize the pharmacokinetics and immunogenicity of lacutamab. At the data cut-off, 10 patients were treated with lacutamab. Median age was 71.0 years (range: 61-77), median prior lines of therapies was 3 (range: 1-5), and median follow-up was 1.9 months (m) (range: 0.5-8.8 m). The majority (90%) of treatment-emergent adverse events (TEAEs) were of grade 1-2 severity, grade ≥3 related TEAEs were observed in 2 (20%) patients: 1 with serum sickness, and 1 with aspartate aminotransferase elevation. No serious TEAEs were observed and none of the patients discontinued study drug due to TEAE. Overall, preliminary Phase 1b data in patients with R/R PTCL confirm the acceptable safety profile of lacutamab monotherapy. The preclinical activity profile improves when assessed in combination. These data inform the future development of lacutamab to provide additional therapeutic options that may improve outcomes for PTCL patients, including those who relapse or are refractory to available therapies. A Phase 2 study evaluating the combination of lacutamab with GemOx is ongoing (NCT04984837) based on pre-clinical observations that GemOx improves lacutamab-induced ADCC by NK cells.

Pre-treatment 18f-FDG PET/CT for Assessing and Predicting Bone Marrow Involvement in Patients with Newly Diagnosed Peripheral T-Cell Lymphoma

Objective: To explore the value of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in assessing and predicting bone marrow involvement (BMI) in patients with newly diagnosed peripheral T-cell lymphoma (PTCL) prior to treatment. Methods: This retrospective study included 201 eligible patients of PTCL who received bone marrow biopsy (BMB) and PET/CT between January 2017 and December 2022. Extra subgroup analysis was designed considering the variation of avidity of FDG in different distinct entities. The status of bone marrow (BM) by PET was assessed using a visual examination and a quantitative index (the highest SUV of BM divided by the mean SUV of the liver [M/L]). Prognostic value of BM findings was also evaluated regarding progression free survival (PFS) and overall survival (OS). Results: The sensitivity and specificity of PET/CT for patients with confirmed PTCL by BMB were 43.2% and 90.2%, respectively. As for subgroup analysis, the kappa value reflecting the agreement between BMB and visual analysis in angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALCL) as well as nodal T-follicular helper (TFH) cell lymphoma (PTCL-TFH) was 0.315, 0.307, 0.426 and 0.581, respectively. (Give the number of cases in each lymphoma group) PET score was an independent factor for PFS (P =0.011) but not for OS (P =0.840). In addition, 25 patients with stage I to II disease had no evidence of BMI by either PET/CT or BMB. Image-guided biopsy was also recommended when PET/CT showed a focal FDG uptake outside the iliac crest. Quantitative analysis revealed the differences in the two-level of M/L; however, they were not statistically significant for both PFS and OS (P =0.246 and P =0.227). Conclusion: PET/CT has a complementary role in assessing BMI and prognosis in PTCL patients.

Red Cell Distribution Width-to-Albumin Ratio Is a Simple but Robust Prognostic Biomarker in Peripheral T-Cell Lymphoma

Background: Red cell distribution width (RDW) is the difference in the volume and size of erythrocytes. High RDW has been identified as a worse prognostic factor in various diseases, including sepsis, cerebrovascular accidents, and diverse cancers. More recently, RDW-to-albumin ratio (RAR) is a comprehensive biomarker combining inflammation and nutrition status that better reflects a patient's frailty. However, little is known about its prognostic relevance in peripheral T-cell lymphoma (PTCL), with only one publication focusing on RDW (Castro et al.). Methods: This retrospective analysis included consecutive patients with newly diagnosed PTCL between 2007 and 2023 at Kameda Medical Center. Extranodal NK/T-cell lymphoma, adult T-cell leukemia/lymphoma, and ALK-positive anaplastic large cell lymphoma were excluded due to distinct prognosis and treatment strategies. The RDW coefficient of variation (RDW-CV) was assessed prior to treatment and calculated using the following formula: 1 standard deviation of mean corpuscular volume (MCV) divided by MCV, multiplied by 100. Receiver operating curve (ROC) analysis was used to determine the optimal cutoff value of RDW-CV and RAR for 2-year outcomes. Survival analyses were conducted using Kaplan-Meier curves with log-rank tests, and Cox proportional hazard models were used for univariate and multivariate analyses. Results: In total, 115 patients were included in this analysis. The median age was 74 years (range 45-93), with male predominance (60.8%). Sixty-five patients (56.5%) were initially treated with the CHOP regimen, while 29 patients (25.2%) received more intensive chemotherapy. The most common disease subtype was PTCL-not otherwise specified (49.5%), followed by angioimmunoblastic lymphoma (40.0%). The median RDW-CV and RAR were 14.8 (range 12.2-21.5) and 4.61 (range 2.6-9.8), respectively. The RDW-CV was significantly correlated with levels of hemoglobin (R = -0.4), albumin (R = - 0.59), and lactate dehydrogenase (R = 0.27) (all P &amp;lt; 0.05). ROC curve analysis for 2-year survival revealed a higher area under the curve (AUC) for RAR (0.79) compared to RDW (0.74), with cutoff values of 4.4 and 14.1, respectively (Figure 1). Using this cutoff value, patients with high RAR had significantly worse overall survival (OS) and progression free survival (PFS) than those without (2-year OS rate: 82.5% vs. 35.1%, Figure 2; 2-year PFS rate: 54.8% vs. 27.9%, P &amp;lt;0.001). On multivariate analysis, high RAR was associated with a significantly worse PFS (hazard ratio [HR] =1.89 [95% confidence interval 1.15-3.11], P =0.01) and OS (HR=3.02 [1.66-5.50], P &amp;lt;0.001) independent of the international prognostic index (IPI), dose reduction of chemotherapy and lymphoma subtype. Conclusion: We demonstrated that RAR improved the prognostic stratification compared to RDW-CV alone. Additionally, baseline high RAR was identified as a simple but robust prognostic factor independently associated with IPI category and treatment intensity in PTCL patients.

Genome-Wide CRISPR Screen Identifies ZNF451 Regulating Sensitivity to Topoisomerase 2 Inhibitors in Peripheral T-Cell Lymphoma Cells

Introduction: Despite the recent therapeutic developments for peripheral T-cell lymphomas (PTCLs), their prognosis remains dismal. Topoisomerase 2 inhibitors (TOP2i), which increase the amount of TOP2-DNA covalent complex and block DNA double-strand break repair, have long been used as key drugs in the treatment of PTCLs. The molecular mechanisms underlying sensitivity to TOP2i remain to be fully elucidated. Methods: To elucidate the cell-intrinsic genes affecting TOP2i sensitivity in PTCL cells, we performed whole-genome loss-of-function CRISPR screenings in adult T-cell leukemia/lymphoma (ATLL) cell lines. ST1 and KK1 cells were transduced with the Brunello CRISPR knockout pooled library targeting 19,114 genes (4 sgRNAs/gene) followed by puromycin selection. The transduced cells were then treated with etoposide (ETP), doxorubicin (DOX) or DMSO control for 8 days. The MAGeCK algorithm was used to rank the sgRNAs responsible for TOP2i sensitivity. Among the top 500 enriched genes, we further selected the those with at least 2 sgRNAs with a log2 fold change (TOP2i/DMSO) &amp;lt; -0.5 or &amp;gt;0.5 in both ST1 and KK1 cells as genes whose knockout conferred TOP2i sensitivity or resistance, respectively. Results: Using the whole genome loss-of-function CRISPR screen, we identified 3 genes and 2 genes whose knockout conferred ETP sensitivity and resistance, respectively. TOP2A, a known ETP target, was ranked as a top gene for ETP resistance, confirming the reliability of our screenings (Fig. 1). In the same way we also extracted 3 genes whose knockout conferred DOX sensitivity. Interestingly, zinc finger protein 451 (ZNF451) was identified as an overlapping gene whose knockout conferred sensitivity in both screens for ETP and DOX. ZNF451 is an E3 SUMO ligase and was previously reported to be an endogenous DNA repair factor for TOP2i-induced DNA double-strand breaks (Schellenberg et al. Science 2017). The role of ZNF451 in PTCL cells has not been previously reported, prompting us to focus on ZNF451 in further analyses. For a confirmatory experiments, we transduced sgRNAs targeting ZNF451 (sgZNF451) in ATLL cell lines. To see the knockout efficiencies of the sgZNF451, we performed immunoblot analysis by using anti-ZNF451 antibody and found three bands with different levels of reduction. To ensure whether the bands detected by the anti-ZNF451 antibody represented endogenous ZNF451 protein, we engineered the ATLL cell line with an HA-tag at the 5' UTR of the endogenous ZNF451 gene locus by CRISPR-mediated knock-in. Immunoblot analysis of sgZNF451-transduced engineered cells expressing HA-tag-ZNF451 by using anti-HA antibody showed almost the same pattern of the bands as shown in the blot by anti-ZNF451 antibody. Thus, we confirmed that sgZNF451 worked efficiently and concluded that post-transcriptional modification affected the stability of ZNF451 protein in ATLL cells. Next, we investigated the role of ZNF451 on cell viability. While sgZNF451-transduced ATLL cells did not differ from control sgRNA-transduced cells in terms of cellular proliferation under normal culture conditions, sgZNF451-transduced ATLL cells showed increased sensitivity to both ETP and DOX compared to control cells with statistical significance, confirming our screening results (Fig. 2). Importantly, sgZNF451-mediated sensitization to ETP and DOX was found not only in ATLL cells but also in other PTCL cell lines including ALK-positive and ALK-negative anaplastic large cell lymphoma (ALCL). Mechanistically, apoptosis and G2/M cell cycle arrest were induced at significantly higher frequencies by ETP treatment in ZNF451 knocked out cells compared to control cells. Given the role of ZNF451 in TOP2i sensitivity in PTCL cells, we investigated whether ZNF451 expression levels stratify the prognosis of PTCL patients treated with CHOP-like regimens. To test this, FFPE samples from 45 PTCL-NOS patients were used for Q-PCR analysis of ZNF451 mRNA but we did not find any correlation between the ZNF451 expression and prognosis. Conclusions: We performed unbiased genome-wide CRISPR/Cas9 library screens and identified ZNF451 as an important regulator of sensitivity to TOP2i in PTCL cells. Further studies are needed to determine whether measuring ZNF451 protein levels can be used as a biomarker in PTCL patients who are treated with TOP2i.

Significance of the Rhoa G17V Mutation Detected By Ddpcr in Diagnostic and Monitor of Angioimmunoblastic T-Cell Lymphoma

Introduction Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma (PTCL) that originates from T follicular helper cells (TFH). RHOA G17V mutation is the most common hotspot locus which could be detected in 50%-70% of cases, showing its potential value for the diagnosis and clinical monitor of this disease. Methods RHOA G17V mutation were detected by Droplet digital PCR (ddPCR) in available samples from PTCL patients, at baseline and before every cycle. Response assessments were done by PET/CT and evaluated according to Lugano criteria after 3 cycles and end of first line chemotherapy(EOT), or at suspicious of disease progression. All data analyses were performed using SPSS 20.0 software (SPSS, Inc.) and GraphPad Prism 9.0 software (GraphPad software). p-Value &amp;lt; 0.05 was considered statistically significant. Results 30 patients with PTCL were included in our center from 2021-01-01 to 2023-07-01,21 were confirmed as AITL and 9 were PTCL-NOS by pathologist review. In whole cohort, RHOA G17V mutation could be detected in 46.7%(14/30) of all patients, also was positive in 61.9%(13/21) and negative in 38.1% (9/21) of patients with AITL. The sensitivity and specificity of RHOA G17V mutation in AITL by ddPCR is 61.9% and 88.9%, with a positive predictive value of 92.9%, and a negative predictive value of 50%. Hyperglobulinemia, positive direct Coombs test, elevated LDH, elevated β2-MG were founded in 76.9%(10/13),61.5%(8/13) ,61.5%(8/13) and 76.9% (10/13) of AITL patients with RHOA G17V mutation, which were significantly higher than those without RHOA G17V mutation(P=0.002,0.019,0.019,0.026). Furthermore, all of the of RHOA G17V mutated AITL patients were in clinical stage III or IV(100%, 13/13), 76.9%(10/13) of them with detectable whole-blood EBV-DNA(≥500 copies/mL) and all have three or more TFH markers(100%,13/13). We next evaluated the baseline and dynamical changes in RHOA G17V VAF-positive patients with AITL. Pretreatment VAF was significantly lower for patients who achieved complete remission or partial remission at EOT compared with that of patients with progressive disease or stable disease (mean VAF, 20.75% vs. 4.31%, p = 0.0028). (Figure 1). In addition, the median PFS in AITL patients with and without RHOA G17V mutation was 9.157 months and 15.154 months respectively(P=0.32).Finally, in 10 AITL patients with dynamic results of RHOA G17V mutation (Figure 2) , a good correlation was found in between dynamic changes of VAF of RHOA G17V mutation and response assessment by PET/CT, rerise of RHOA G17V mutation VAF could be detected prior to clinical progression in two patients，showing for the its protentional value for disease monitor. Conclusions Our study first reported the diagnostic value of single hotspot detection of G17V RHOA mutation by ddPCR in PTCL. Monitoring of G17V RHOA mutation in AITL has predictive value of assess tumor burden and response, also can complement the longitudinal supervise of disease.