Peripheral T-cell Lymphoma Patients Research Articles

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 < 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 < 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 <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 <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) < -0.5 or >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 < 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.

Selinexor in Combination with Salvage Regimen for Refractory Peripheral T-Cell Lymphoma (PTCL) Patients

Background Peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS) are a diverse and aggressive type of non-Hodgkin lymphomas with a poor prognosis when treated with conventional chemotherapy. The standard CHOP chemotherapy regimen typically yields an overall response rate (ORR) of 60-80%, a complete response (CR) rate of 30-40%, and long-term survival, measured by 5-yr OS，in the range of 20-30% in non-ALCL (anaplastic large cell lymphoma) subtypes. Azacitidine plus CHOP has achievied a 75% CR in newly diagnosed PTCL, but patients with DNMT3A mutation showed adverse progression-free survival (PFS), indicating that genetic mutations may influence resistance to chemotherapy. Selinexor has shown promising results in refractory lymphoma patients by inhibiting oncogenes, therefore, the efficacy of selinexor combined salvage regimen in refractory PTCL remains great interest. Method Refractory PTCL patients were enrolled to be treated with selinexor plus GDP/ICE/Gemox since December 2021 at our center. Selinexor was administered orally (40 mg day 1, 8, 15) plus GDP (gemcitabine 1g/m2*d1, cisplatin 25mg/m2 d1-d3, dexamethasone 40mg d1-d4), ICE (ifosfamide 1.5g/m2*3d, carboplatin (AUC 5) and etoposide 100mg/m2*3d), Gemox (gemcitabine 1g/m2*d1, oxaliplatin 100mg/m2*d1) every 3 weeks as per physician's choice. Objective response rate (ORR) was evaluated every 3 cycles based on Lugano 2014 criteria and Adverse events (AE) were rated according to the NCI CTCAE 5.0. Results 10 patients were treated with selinexor plus salvage regimen in this study and received more than two cycles of the treatment, making them eligible for response evaluation in this poster. The median age of the 10 patients was 65 years (range from 42 to 79), 8 (80%) were male, 9 (90%) had disease stage III-IV at screening, and 60% of all patients had an IPI intermediate to high risk. All of the patients were refractory to the last line of treatment. Among 10 patients, 2 were angioimmunoblastic T-cell lymphoma (AITL), 3 with PTCL-NOS, 3 with ALK-ALCL, 2 with monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). As shown in Figure 1, 3 patients had TP53 alterations, 2 patients with DNMT3A mutation. Patients received a median of three cycles (range, 2-6) of selinexor 40mg once a week combined with salvage regimen（4 patients received Selinexor-GDP, 3 with selinexor-ICE, 3 with selinexor-Gemox）. The best overall and complete response rates were 70% and 50%, respectively. In terms of MEITL refractory to conventional CHOP treatment, 1 achieved PR but progressed and died after stop treatment for three months due to Covid19 and 1 in CR with selinexor maintenance. Conclusions There are limited options for the treatment of refractory PTCL. We identified a dosing schedule of selinexor (40mg qw) with GDP/ICE/Gemox that is efficiency inrefractory PTCL and is worthy of further study on its mechanism of action.

Prognostic Significance of CD30 Expression and Response to Brentuximab Vedotin in Patients with Angioimmunoblastic T Cell Lymphoma

Background Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma (PTCL) characterized by a follicular helper T-cell phenotype. The standard frontline treatment for AITL typically involves CHOP or CHOP-like regimens, with consideration for autologous stem cell transplant. A promising treatment option for CD30-positive (CD30+) PTCLs, including AITL, is the anti-CD30 antibody drug conjugate, brentuximab vedotin (BV). The ECHELON-2 study demonstrated equivocal outcomes in CD30+ PTCL patients (pts) who received BV-CHP instead of CHOP. However, response of BV in CD30+ AITL pts is still uncertain. This study aims to evaluate the relationship between CD30 expression and the clinical response to BV in pts diagnosed with AITL. Methods This retrospective IRB approved study conducted at MD Anderson Cancer Center, where we analyzed pts with AITL diagnosed between 1997- 2023. Patient demographics, laboratory data at diagnosis, pathology review, treatment, and treatment response were collected and analyzed. Expression of CD30 expression in neoplastic cells was evaluated by immunohistochemistry and scored in 5% increments. Kaplan- Meier method was used to assess overall survival (OS) and log-rank used to compare different groups. Results This study included a cohort of 339 pts with AITL. Among them, 55 (23%, n=237) had no detectable CD30 expression (CD30=0%),182 (77%, n=237) patients had detectable CD30 expression (CD30>1%), and 102 pts had unknown CD30 expression. Table 1 shows patient characteristics by CD30 expression and response to first-, second-, and third- line BV treatment. There were 113 (48%, n=237) females and 124 (52%, n=237) males with a median age of 66 years. Most patients were Whites (88%, n=196) followed by Black (4%, n=196), and Asian (5%, n=196). Fifty-two (n=122) of pts who were CD30+ had stage III, 43% (n=122) had stage IV (p-value= <0.001), and 38% had BM involvement (p- value= 0.3). For pts with disease showing no CD30 expression (CD30neg) 16% (n=43) of pts had stage III, 70% (n=43) had stage IV, and 48% (n=42) had BM involvement. Auto-Stem cell transplant (ASCT) was performed in 48% of those with CD30+ and 43% of CD30neg. The most common first-line treatment was chemotherapy combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) followed by other CHOP like regimens. In total, 35 pts received BV treatment as first-line, 32 patients received BV in combination with chemotherapy and 3 received BV only. For second-line treatment, 11 received BV treatment and for third- line only 6 received BV. First- line treatment with BV showed better clinical response rates, with 82% achieving complete response (CR, n= 34), followed by second line CR with 56% (n= 9) and third- line with 0% (n= 6). The median OS were similar between those with CD30+ who did or did not receive first line BV (20 months vs. 19 months, p>0.05). The median OS for CD30neg pts who did not receive BV was 25 months (p=0.42). Furthermore, there was no statistically significant difference in OS between pts who underwent a ASCT (CD30+ 24.5 months and CD30neg 32.5 months, respectively) and those who did not (CD30+ 18.5 months and CD30neg 24.5 months, respectively, p- value = 0.29). Conclusion While this study did not find CD30 expression to be a predictor of response to BV treatment or ASCT in AITL pts, it provides valuable insights into the prevalence of CD30 expression and BV response as first- line treatment. Notably, 77% of pts had CD30 expression and pts who received BV as first- line had a higher proportion of CRs compared to pts who received BV as second- and third- line treatments. Further investigations with larger patient cohorts are necessary to determine the prognostic and predictive role of CD30 in AITL. Additional studies analyzing CD30 expression levels in malignant cells, immunoblasts, and macrophages are planned for presentation at the upcoming annual meeting.

Azacitidine for Injection Combined with Chidamide in Relapsed/Refractory Peripheral T-Cell Lymphoma: A Phase I Study

Background: Peripheral T-cell lymphoma (PTCL) is a group of highly heterogeneous malignant tumors with poor prognosis, especially in patients with relapesd/refractory. The efficacy of traditional salvage chemotherapy in the treatment of Relapsed/Refractory (R/R) PTCL was poor, and the median OS and PFS after the first recurrence or progression were only 5.5 months and 3.1 months, respectively. There is an urgent need for more effective treatment regimens to improve the poor prognosis of these patients. Epigenetics, as a new discipline involved in gene expression regulation, provides a new approach for the occurrence, development mechanism research and clinical diagnosis and treatment of PTCL.This phase I study is a prospective, single center clinical study and designed to evaluate the safety, tolerability and efficacy of Azacitidine for injection combined with Chidamide in Relapsed/Refractory peripheral T-cell lymphoma. Methods: Eligible pts (18-75 years of age, ECOG PS 0-2) had histologically confirmed peripheral T-cell lymphoma that was either relapsed or refractory to at least 1 line of therapy. Considering that both Dose Group 2 (Azacitidine 75mg/m 2, Chidamide 20mg) and Group 3 (Azacitidine 50mg/m 2, Chidamide 30mg) adjust the dosage of a single drug based on Dose Group 1 (Azacitidine 50mg/m 2 ih d1-7, Chidamide 20mg po biw; 4 weeks/cycle), this study derived a “3+3” two-dimensional dose increasing design based on the classic “3+3” design, which allows two Dose Groups (Dose Group 2 and Group 3) to start ramp up trials simultaneously according to random principles. Enrollment in dose group 4(Azacitidine 75mg/m 2, Chidamide 30mg) can begin when either group 2 or 3 completes and no DLT occurs. The primary objectives of this study were to evaluate the safety and preliminary anti-tumor activity of Azacitidine for injection combined with Chidamide according to the Lugano 2014 criteria. Adverse events (AEs) were reported according to CTCAE v5.0. Results: Nineteen R/R PTCL pts (median age: 61 years, range: 52-71 years; male: 11 (57.9%) pts; ECOG PS=0: 10 (52.6%) pts) who was either relapsed or refractory to at least 1 line of therapy (median therapy lines:2) were enrolled. Among them, 11 pts were angioimmunoblastic T-cell lymphoma (AITL) and 8 pts were PTCL, NOS. 16 pts could evaluate the efficacy and safety. For 16 treated patients, treatment-related adverse events (TRAEs) of any grade occurred in 15 (93.7%) pts, ≥3 TRAEs occurred in 7 (43.8%) pts. The most frequent TRAEs (≥ 20%) were Pain at the injection site (n=12, 75.0%), Neutropenia (n=9, 56.3%), Erythema at the injection site (n=8, 50.0%), Nausea (n=7, 43.8%), Thrombocytopenia (n=6, 37.5%), Feeble (n=6, 37.5%), Anemia (n=5, 31.3%), Diarrhea (n=5, 31.3%), Neutropenia with fever (n=4, 25.0%). The most frequent grade ≥ 3 TRAEs (≥5%) was Neutropenia (n=3, 18.8%). 3 pts experienced TRAE leading to drug dosage adjustment. The recommended phase II dose (RP2D) was Azacitidine 75mg/m2, Chidamide 20mg (Dose Group 2). As of data cut-off date, 3 pts remained on Azacitidine for injection combined with Chidamide therapy. The objective response rate (ORR) and disease control rate (DCR) were 56.25% (9/16; 95% CI: 31.9-80.5) and 75% (12/16; 95% CI: 53.8-96.2), respectively. For AITL pts, the ORR was and DCR were 60% (6/10; 95% CI: 36.0-84.0) and 80% (8/10; 95% CI: 60.4-99.6), and 4 pts achieved CR. For all PTCL pts enrolled, Median PFS 6.45 months (95% CI: 3.97-12.7); Median OS 17.5 months (95% CI: 2.11-32.9). Conclusion: Azacitidine for injection combined with Chidamide showed a promising anti-tumor effectivity with a manageable safety profile in Relapsed/Refractory peripheral T-cell lymphoma patients, especially for AITL patients.

Development and Characterization of a Novel Murine Peripheral T-Cell Lymphoma Cell Line Which Closely Mimics Human Disease

Peripheral T-cell lymphoma (PTCL) represents a heterogenous group of aggressive non-Hodgkin lymphomas with poor prognostic outcomes and limited treatment options. Despite the advances in genomic sequencing and molecular characterization, the complex and elusive nature of PTCL's underlying biology has proven difficult to fully understand and manage effectively. The development and refinement of therapeutic strategies for PTCL are impeded by a paucity of reliable preclinical models that accurately mimic the disease's pathophysiology. There is a dire need for more physiologically relevant models for PTCL. Improved models allow for a better understanding of the disease's molecular and cellular mechanisms, facilitate the development of innovative therapeutic strategies, and ultimately improve patient outcomes. Here we described a new T-cell lymphoma cell line (LM-23) derived from a 12-week-old female Balb/cJ mouse which developed diffuse adenopathy and splenomegaly. Tumors from this mouse were cultured in cRPMI + 10% fetal bovine serum for 4 weeks without supplementation of additional cytokines and passaged 3-4 times per week where we found the cells to be non-adherent. Immunophenotyping of LM-23 demonstrated positivity for CD90, CD3, TCR-beta, CD4(partial/subset), CD8, PD1 (positive), ICOS (positive) and negative for B-cell and myeloid lineage markers (Fig. 1B). This immunophenotype most closely resembles PTCL-NOS in humans at an immunophenotypic characterization level. Whole exome sequencing is in progress and will be presented. Intravenous administration of this cell line to syngeneic Balb/cJ mice resulted in rapid establishment of diffuse adenopathy, splenomegaly, and liver metastases. Bulky adenopathy was observable within 14 days of administration. Histologically, these tumors consisted of sheets of medium to large sized lymphocytes with clumped chromatin and prominent nucleoli, similar to human T-cell lymphomas (Fig. 1A). Subcutaneous administration demonstrated rapid tumor growth with mice reaching terminal endpoints (>2,000mm 3) within 21 days following administration. As CHOP-based (cyclophosphamide, doxorubicin, vincristine, and prednisone) therapies are the primary backbone for treatment of PTCL, we tested whether CHOP therapy alone had anti-tumor activity to LM-23. Tumor bearing mice (~150mm 3) were treated with CHOP and monitored for tumor growth. All mice treated were non-responsive to CHOP therapy with no difference in tumor growth compared to untreated mice. Additionally, LM-23 bearing mice treated with anti-PD1 showed signs of hyperprogression, which has been observed in human patients in clinical trials (Gao Y et al. JCI Insight 2023, Bennani NN et al. Blood Supplement 2019). Additional therapeutic target testing is underway and will be presented. In conclusion, the newly established LM-23 T-cell lymphoma cell line provides a novel, physiologically relevant preclinical model for the study of PTCL. Its phenotypic characteristics, rapid growth, and metastatic behavior in syngeneic mice, along with its resistance to CHOP therapy and hyperprogression upon anti-PD1 treatment, mimicking the clinical scenarios observed in some human PTCL patients. These features highlight LM-23's potential as a valuable tool for understanding the biological mechanisms underlying PTCL and for the development and testing of innovative therapeutic strategies. We hope that the LM-23 cell line will contribute significantly to these efforts, ultimately improving outcomes for patients afflicted with PTCL.

TBI/Ratg-Based Conditioning for Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation in 11 Cases of Chemotherapy-Resistant Advanced-Stage Peripheral T-Cell Lymphoma

Objectives: To evaluate the clinical outcomes and safety of haploidentical allogeneic hematopoietic stem cell transplantation(haplo-HSCT)with total body irradiation (TBI)/rabbit Anti-thymocyte globulin (rATG) based conditioning regimen in chemotherapy-resistant advanced-stage peripheral T-cell lymphoma (PTCL). Methods: From September 2019 to December 2022, eleven chemotherapy-resistant advanced-stage PTCL patients who underwent haplo-HSCT were enrolled in our study. All of them received TBI/rATG-based conditioning regimen in our centers. Results: ①Among 11 patients, there were 6 males and 5 females with a median age of 40(range：22~58) years old. Six cases of them are peripheral T-cell lymphoma not otherwise specified (PTCL NOS), 3 cases are angioimmunoblastic T-cell lymphoma (AITL), 1 case is large-cell transformation of mycosis fungoides (MF-LCT), and 1 case is T-cell large granular lymphocytic leukemia(T-LGLL). The Lugano stage was III or IV in all cases, and 8 patients had B symptoms. The median number of previous chemotherapy exposure before transplantation was 4 (range: 2~10) lines and the disease status before transplantation was progressive diseases (PD) in all cases. The median time from diagnosis to transplantation was 17(range：6~36) months.②The conditioning regimen consisted of TBI 2Gy d-8, 4Gy from day-7 to -6, rATG 2.5 mg/kg/d day-5 to -2, etoposide 15mg/kg/d day-5 to -4, cyclophosphamide (CTX) 50mg/kg/d, day-3 to -2. The patients with central nervous system involvement received a regimen of thiotepa 5 mg/kg/d， from day -5 to -4 instead of CTX and etoposide, and add 2.0 g/m2 of cytarabine twice a day, from day -3 to day -2 into the conditioning.③All patients were successfully engrafted. Only one patient developed Grade III-IV acute graft-vs-host disease (aGvHD). Among the 8 survivors, 4 cases developed chronic graft-vs-host disease (cGvHD).④After transplantation, CR was obtained in 9 patients. ⑤Regimen related toxicities: all were non-fatal. Hematopoietic suppression occurred in all patients after conditioning. Three patients had diarrhea and four had mucositis and three had elevated transaminase/bilirubin levels. Seven patients had infections.⑥The 1-year cumulative non-relapse mortality (NRM) and 1-year cumulative incidence of relapse (CIR) was 22.5±14.0% and 20.2±12.7%, respectively. The 1-year overall survival (OS) and 1-year disease-free survival (DFS) was 72.7±13.4% and 63.6±14.5%, respectively Conclusions: TBIand rATG based conditioning regimen is effective and safe for haplo-HSCT in chemotherapy-resistant advanced-stage PTCL.

Expression of PD-1/PD-L1 in peripheral blood and tumor tissues of patients with classical Hodgkin's lymphoma.

Significant biomarkers can predict and estimate the response to chemotherapy for different types of lymphoma. Classical Hodgkin's lymphoma (cHL) and peripheral T-cell lymphoma (PTCL) belong to different types of lymphoma, their prognosis is very different, programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) have been studied in these 2 types of diseases. However, few studies have involved the difference in PD-1/PD-L1 levels between cHL and PTCL. To find out the difference and relevant clinical application value, we collected blood samples of 29 newly diagnosed cHL patients and 11 newly diagnosed PTCL ones. At the same time, tumor tissue paraffin sections of 13 patients with cHL were collected at the initial diagnosis. Flow cytometry, enzyme-linked immunosorbent assay, and immunohistochemical staining were used to detect PD-1/PD-L1 levels in peripheral blood T cells, plasma, and tumor tissues, and the relationship between the above results and clinical data of patients in patients with cHL were investigated. The levels of PD-1 on CD4+ T cells, PD-L1 on CD4+ T cells and PD-1 on CD8+ T cells in peripheral blood of cHL and PTCL patients were higher than those of healthy controls, the level of PD-1 in CD4+ T cells from peripheral blood was higher from cHL patients with stage III-IV (P = .0178), B symptoms (P = .0398), higher lactate dehydrogenase (P = .0056), higher international prognostic index score (P = .0349), and relapsed in later stages (P = .0306). The expression level of soluble PD-L1 (sPD-L1) from cHL (P < .001) and PTCL (P < .0001) patients was higher than that of the healthy control group, and there was higher sPD-L1 level in patients with higher international prognostic index scores (P = .0016). The dynamic detection of sPD-L1 showed that after 2 courses of chemotherapy, the sPD-L1 level in cHL patients with complete remission declined, but the level of sPD-L1 from patients with incomplete remission was not significantly changed (P > .05). In tumor tissues of cHL patients, PD-1(+) was 77%, PD-L1(+) was 69%, PD-1 and PD-L1 expression levels were high. Our results suggest that PD-1 levels in peripheral blood CD4+ T cells are helpful for the stage of disease in patients with cHL, and the dynamic detection of sPD-L1 level is helpful for the judgment of patients with cHL.

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.

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.

Chidamide with Azacitidine and CHOP Treatment Plus Autologous Transplantation,Followed By Maintenance with Chidamide for Patients with Newly Diagnosed Peripheral T-Cell Lymphoma: Interim Analysis of a Prospective,Single Center,Single-Arm, Phase 2 Trial

Background: The standard first-line treatment for peripheral T-Cell Lymphoma (PTCL) is cyclophosphamide, doxorubicin, vincristine, and prednison (CHOP)，but the treatment effect is poor,the 5-year overall survival(OS) was only 30-40%.We aimed to evaluate the efficacy and safety of chidamide with azacitidine and CHOP treatment plus autologous stem-cell transplantation and of maintenance treatment with chidamide in newly diagnosed peripheral T-Cell Lymphoma (PTCL). Methods: This is an ongoing prospective,single center，single-arm, phase 2 trial. We enrolled newly diagnosed PTCL patients (NK/T lymphoma and ALK positive T cell lymphoma were excluded )and used 21-day Chi+AZ-CHOP regimen for induction therapy.Subjects received CHOP on day 1 combined with azacitidine 100mg was subcutaneous injected daily for 5 days and oral chidamide 20mg two times per week of each cycle. 17 subjects received PEG-rhG-CSF Supportive care after treatment.These subjects who evaluated PR or CR remission after 4 to 6 courses of induction therapy will perform autologous hematopoietic stem cell transplantation(ASCT), followed by oral chidamide 20mg two times per week maintance. The primary endpoints is ORR per 2014 IWG criteria.Secondary endpoints include CR, safety and survival. Results:From 3/2021 to 7/2023, 35 subjects with previously untreated PTCL were enrolled in chongqing university cancer hospital, and the study met its accrual.At study entry, 22 patients (62.8%) were angioimmu-noblastic T-cell lymphoma(AITL),4 patients (11.4%) was monomorphic epitheliotropic intestinal T-cell lyphomas(MEITL),3 patients (8.6%) were Peripheral T Cell Lymphoma, Not Otherwise Specified（PTCL-nos），2 patients (5.7%) was Mycosis fungoides(MF),4 patients(11.4%) was anaplastic large cell lymphoma; ALK-negative（ALCL-ALK).The median age was 55 years (range 27-70),and the M:F ratio was 1.5:1. 26 patients (74.3%) had stage Ⅲ/Ⅳ disease, 6 (17.1%) had bone marrow involvement, and 11 (31.4%) had IPI 3-5.By July 2023, 3 subjects did not return to the hospital for further treatment after the first cycle. 32 subjects received Chi+AZ-CHOP regimen treatments at least 2 cycles,median treatment cycles were 4 cycles. 2 subjects progressed during the treatment, 10 subjects were performed with autologous hematopoietic stem cell transplantation. The ORR was 87.5% with CR at 46.9%(n=32) .The assessment after autologous hematopoietic stem cell transplantation(n=10), ORR was 100 % and CR was 90%.To date, Evaluation of outcomes in patients with AITL at the end of induction(n=17), ORR was 94.1% and CR was 52.9%. Treatment was generally well tolerated with expected side exects.The most common grade 3-4 hematologic adverse events were neutropenia（45%），febrile neutropenia (40%)，anemia (25%) and thrombocytopenia (15%) ,Grade 3-4 non-hematologic toxicities included hypokalemia（35%）,nausea(30%), vomiting (20%),fatigue (30%),and elevated ALT (4.8%).No treatment-related deaths have been studied so far. C onclusion: This trail proved that chidamide combined with azacytidine +CHOP is feasible and safe in the treatment of peripheral T-cell lymphoma. Especially，achieved a high CR rate in the induction therapy phase of AITL subtype. Although neutropenia is the most common adverse reaction, it is generally safe and controllable.

High Rates of Remission with the Initial Treatment of Oral Selinexor Plus CHOP for Newly Diagnosed Peripheral T-Cell Lymphoma (PTCL): Clinical Outcomes Analysis of a Multi-Center Phase II Study in China

CONCLUSIONS Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of aggressive lymphoproliferative disorders with dismal clinical outcomes. In China, PTCLs account for over 20% of non-Hodgkin lymphoma (NHL) cases, representing a relatively high incidence. Although CHOP-like regimens remain the standard frontline therapy, their efficacy is limited (Alain Mina, 2022). Previous studies have demonstrated high expression of XPO1 in T-NHL cell lines and potent anti-proliferative effects of the selective inhibitor selinexor at nanomolar concentrations (Abeykoon JP, 2019). Here, we report the safety and preliminary efficacy of combining selinexor with CHOP as first-line treatment in previously untreated PTCL patients (ChiCTR2200057942). In this open-label, multicentre, phase 2 trial, we enrolled patients with previously untreated peripheral T-cell lymphoma (PTCL). Participants received standard CHOP chemotherapy on day 1 of each cycle for 6 or 8 cycles, along with selinexor priming at 40 or 60 mg on days 1, 8 and 15. Patients achieving a complete response (CR) or partial response (PR) at the end of induction treatement (EOI), with or without autologous stem cell transplantation (ASCT), and then received maintenance treatment with selinexor (days 1, 8, 15 and 22 every 28 days) for up to 12 months. The primary endpoint was overall response rate (ORR) during induction, and secondary endpoints included CR rate, duration of response (DOR), PFS, OS and safety. Between Jul 1, 2022 and May 21, 2023, a total of 17 previously untreated PTCL pts were enrolled and received treatment at six centers, including seven with AITL (41.2%), six with PTCL-NOS (35.3%). The median age was 52 years (range 30-67), 11 (64.7%) had stage III/IV disease, with nine (52.9%) pts having IPI 2-5. As of July 10, 2023, with a median follow-up of 7.3 months (range 1.9-14.8 months), three pts discontinued treatment without efficacy evaluation (two pts due to bone marrow suppression, one pt due to COVID-19 infection), and one pt died due to disease progression. Among 12 pts evaluable for the primary endpoint, seven pts (58.3%) achieved CR, four pts (33.3%) had PR, one pt (9.1%) experienced progressive disease (PD). Based on the analysis of different subtype, the ORR and CR was 100% (5/5) and 80% (4/5) in AITL, 100% (4/4) and 25% (1/4) in PTCL-NOS. One ALK+ALCL and one PTCL-TFH patient achieved CR, while one SPTCL patient experienced progressive disease. Among the 12 pts who received the initial dose of 60mg, two pts did not complete the third course of treatment due to myelosuppression, and two pts reduced the dose to 40mg due to adverse reactions. Five pts in the 40mg group did not require dose reduction or withdrawal. The ORR was 87.5% (7/8) and the CR rate was 62.5% (5/8) in the 60 mg group. The ORR was 100% (4/4) and the CR rate was 50% (2/4) in the 40 mg group. Pts in the 40mg group had better tolerance and similar efficacy compared to those in the 60mg group. The most common (≥10%) Grade 3 or 4 treatment-related adverse events (AEs) were neutropenia (29%), thrombocytopenia (24%), and anemia (18%). No fatal AEs were reported at the end of follow-up, the median PFS and OS were not reached. The integration of Selinexor into the standard tri-weekly CHOP chemotherapy regime has shown a manageable safety profile along with encouraging anti-tumor activity in patients with previously untreated PTCL. The trial is currently ongoing, and this manuscript presents the preliminary findings.

Efficacy and Safety Analysis of Combination Therapy Based on Liposomal Mitoxantrone (Lipo-MIT) in Relapsed/Refractory NK/T-Cell Lymphoma

Background: Currently, there is no standard treatment for relapsed/refractory NK/T-cell lymphoma (NKTCL), which is characterized by highly aggressive and poor prognosis. New drugs are urgently needed to improve the therapeutic effect. Liposomal mitoxantrone (Lipo-MIT) is approved in China for the treatment of relapsed or refractory peripheral T-cell lymphoma patients who have received at least one line standard therapy previously. Phase II study data showed that the objective response rate (ORR) of patients after monotherapy was 41.7% and the complete response rate (CR) was 23.1%. Progression-free survival (PFS) was 8.5 months. Lipo-MIT showed excellent anti-tumor effect in patients with NKTCL subtype, with an ORR of 42.9%, which broke the limitation of natural resistance of NKTCL to anthracyclines. To further improve the efficacy, we tried a combination therapy based on Lipo-MIT in patients with relapsed/refractory NKTCL. Herein we will report its efficacy and safety. Methods: Nine patients with relapsed/refractory NKTCL were enrolled in this study, all of whom had previously received pegaspargase-based combination chemotherapy. The salvage treatment was a combination regimen based on Lipo-MIT. The efficacy was evaluated after every 2 cycles using PET-CT or MRI scan, and hematological and non-hematological adverse events were collected after treatment. Progression-free survival (PFS) was defined as the time from initiation of Lipo-MIT to disease progression, recurrence, death, or last follow-up. Overall survival time (OS) was defined as the time from initiation of Lipo-MIT to death from all causes or the last follow-up. Results: The median age of the nine patients was 53 years old (17-67 years old), and the male-female ratio was 7:2. Eight patients had stage IV NKTCL, one was stage II NKTCL, and all patients had an NRI score of ≥3. The median number of previous treatment lines was 2 (1-4). Three patients had recurrent NKTCL, and six patients had refractory disease to previous treatments, among whom two patients had concurrent hemophagocytic syndrome. The salvage treatment regimens were as follows: Lipo-MIT + pegaspargase + dexamethasone (N=3); Lipo-MIT + pegaspargase + dexamethasone +PD1 monoclonal antibody (N=2); Lipo-MIT +PD1 monoclonal antibody + dexamethasone (N=2); Lipo-MIT + etoposide + pegaspargase + dexamethasone (N=2). Efficacy was evaluable in all patients and the median number of treatment cycles was 3 (2-6). The best response rates were as follows: complete response in 3 (33.3%) patients, partial response in 4 (44.4%) patients, stable disease in 1 (11.1%) patient, and progressive disease in 1 (11.1%) patient. At a median follow-up of 4 months (2-13 months), 6 patients died, including 5 from disease progression and 1 from pegaspargase -associated acute pancreatitis, with a median PFS of 5 months and a median OS of 7 months. One patient underwent allogeneic hematopoietic stem cell transplantation after achieving a complete response and has been disease-free for more than 13 months now. The main adverse reactions of Lipo-MIT combination regimen were grade 3 or more bone marrow suppression (N=7), skin cyanosis (N=4), liver insufficiency (N=4), coagulation dysfunction (N=4), acute pancreatitis (N=1). The median recovery time from myelosuppression was 17 days (6-35 days). There was no correlation between skin cyanosis and efficacy. Conclusion: Combination therapy based on Lipo-MIT has a high remission rate for relapsed/refractory NKTCL, but the duration of remission needs to be further extended, and subsequent allogeneic hematopoietic stem cell transplantation may prolong survival. Lipo-MIT has obvious myelosuppression toxicity, and active supportive therapy should be given when combined with other cytotoxic drugs. In the future, it is worthwhile to conduct prospective clinical trials to explore the optimal combination therapy based on Lipo-MIT in relapsed/refractory NKTCL.

Real-world treatment patterns, healthcare resource utilizationand costs among patients with peripheral T-cell lymphoma.

Objective: To evaluate treatment patterns, healthcare resource utilization (HRU)and costs among peripheral T-cell lymphoma (PTCL) patients in the USA. Methods: A retrospective cohort study, using theIQVIA PharMetrics® Plus claims database from 1April 2011 to 30November 2021, identified PTCL patients receiving systemic treatments. Three mutually exclusive subcohorts were created based on line of therapy (LOT): 1LOT, 2LOTand ≥3LOT. Common treatment regimens, median time on treatment, all-cause and PTCL-related HRU and costs were estimated. Results: Among 189 PTCL patients identified, 61.9% had 1LOT, 21.7% had 2LOTand 16.4% had ≥3LOT. The most common treatment regimens in the 1LOT were CHOP/CHOP-like, CHOEP/CHOEP-likeand brentuximab vedotin; monotherapies were most common in the 2LOT and ≥3LOT. All-cause and PTCL-related hospitalizations and prescriptions PPPM increased with increasing LOT. Nearly 70% of total treatment costs were PTCL related. Conclusion: Higher utilization of combination therapies in the 1LOT and monotherapies in subsequent LOTs were observed, alongside high PTCL-related costs.

Autologous hematopoietic stem cell transplantation improves survival outcomes in peripheral T-cell lymphomas: a multicenter retrospective real-world study

The aim of this study is to evaluate the survival benefit of consolidative autologous hematopoietic stem cell transplantation (ASCT) in patients with peripheral T-cell lymphomas (PTCL). In this retrospective study, the ASCT group underwent consolidative ASCT after first-line therapy at 14 transplantation centers in China between January 2001 and December 2019. Data were collected over the same time frame for the non-ASCT group from the database of lymphoma patient records at Peking University Cancer Hospital & Institute. A total of 120 and 317 patients were enrolled in the ASCT and non-ASCT groups, respectively, and their median ages were 43 years and 51 years, respectively. In the ASCT group, 101 patients had achieved complete remission (CR) and 19 patients had achieved partial remission at the time of ASCT. The median follow-up time was 40.2 months and 68 months, and the 3-year overall survival (OS) rate was 80.6% and 48.9% (p < 0.001) for the ASCT and non-ASCT groups, respectively. The beneficial effect of ASCT for OS remained even after propensity score-matched (PSM) analysis (81.6% vs 68.3%, p = 0.001). Among the 203 patients who were aged ≤ 65 years and achieved CR, ASCT conferred a significant survival benefit (3-year progression-free survival [PFS]: 67.4% vs 47.0%, p = 0.004; 3-year OS: 84.0% vs 74.1%, p = 0.010), and this was also maintained after PSM analysis (3-year PFS: 66.6% vs 48.4%, p = 0.042; 3-year OS: 84.8% vs 70.5%, p = 0.011). Consolidative ASCT improved the survival outcome of PTCL patients, even those who achieved CR after first-line therapy.

Efficacy of ex vivo purging with CD34+ selection to maximize the effects of autologous stem cell transplantation in peripheral T-cell lymphoma patients

Background aimsPeripheral T-cell lymphomas (PTCLs) are rare and aggressive tumors with uncertain optimal treatment. This study investigated the clinical outcomes of high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) after CD34+ selective purging in PTCL patients. MethodsRetrospective analysis included 67 PTCL patients who achieved remission and underwent HDT/ASCT. CD34+ selective purging was performed using CliniMACS® (Miltenyi Biotec, Bergisch Gladbach, Germany). Survival outcomes, engraftment, lymphocyte subsets and viral infections were evaluated. ResultsCD34+ selective purged autografts were associated with significantly improved overall survival (OS) and disease-free survival (DFS) compared with unpurged autografts (5-year OS, 73.3% versus 37.8%, 5-year DFS, 73.8% versus 33.4%). The cumulative incidence of relapse was also lower in the purged group (31.5% versus 73.3%). Subgroup analysis revealed significant survival benefits in the high-risk group receiving purged autografts. Lymphocyte subset analysis showed increased natural killer (NK) cell counts in the purged group after ASCT. Higher post-ASCT lymphocyte-to-monocyte ratio (LMR) was associated with improved OS and DFS. ConclusionsCD34+ selective purging in PTCL patients undergoing HDT/ASCT improved survival outcomes and reduced relapse risk. The procedure increased NK cell counts and post-ASCT LMR. CD34+ selective purging may minimize autograft tumor cell contamination and enhance efficacy in T-cell lymphomas.