Refractory Peripheral T-cell Lymphoma Research Articles

Treatment strategies and outcome in relapsed peripheral T-cell lymphoma: results from the Netherlands Cancer Registry

AbstractOptimal treatment in patients with refractory or relapsed peripheral T-cell lymphomas (R/R T-NHLs) is unknown. In this population-based study, outcomes in R/R peripheral T-cell lymphoma not otherwise specified (PTCL NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic lymphoma kinase-positive (ALK+) and ALK-negative (ALK–) anaplastic large cell lymphoma (ALCL) were evaluated. Patients with PTCL NOS, AITL, ALK+ ALCL, and ALK– ALCL (≥18 years) diagnosed in 2014 to 2019 were identified using the Netherlands Cancer Registry. End points were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). The 2-year PFS of 821 patients was 57%. Among 311 patients with a relapse, 243 received second-line treatment: 44% received salvage chemotherapy, 20% received brentuximab vedotin (BV), and 36% received other treatment. In third-line treatment, BV was most commonly used (38%). ORR after second-line treatment was 47%. Two-year PFS and OS after relapse were 25% and 34%, respectively. The risk of second relapse was negatively affected by early relapse (<12 months after diagnosis), whereas BV reduced this risk compared with salvage chemotherapy. Reduced risk of relapse was independent of histological subtype. The best outcomes were observed for patients treated with salvage chemotherapy receiving consolidative autologous and allogeneic stem cell transplantation (SCT) (2-year OS 68%), patients treated with BV achieving a second complete remission (2-year OS 74%) and patients with allogeneic SCT (2-year OS 60%). The risk of second relapse was significantly lower for patients with R/R T-NHL treated with BV compared with patients treated with salvage chemotherapy, and this was irrespective of subtype. Therefore, the use of salvage chemotherapy for patients with R/R T-NHL is challenged.

Abstract 3201: Preclinical development of a novel Romidepsin nanoparticle for the treatment of T-Cell lymphoid malignancies

Abstract The histone deacetylase inhibitors (HDACi) have long been regarded as an important class of drugs for treating T-cell lymphoid malignancies (TCL). Romidepsin (Romi), a bicyclic peptide, was approved for patients with relapsed or refractory cutaneous (CTCL) and peripheral T-cell lymphomas (PTCL). Unfortunately, the approval of Romi for relapsed/refractory PTCL was withdrawn due to a negative Phase 4 post-marketing requirement. Given its potent activity against Class I HDACs, Romi is considered one of the most effective HDAC inhibitors studied and used in patients with TCL. Herein, we report on a first-in-class nanoparticle of Romi (NanoRomi) with a superior safety and efficacy profile compared to the free drug in preclinical models of PTCL and large granular lymphocyte leukemia (LGLL). We developed a first-in-class NanoRomi using our proprietary amphiphilic di-block copolymer-based nanochemistry platform. NanoRomi was characterized in cell viability, flow cytometry, and western blotting (WB) assays to determine the concentration-effect relationships with regard to the induction of apoptosis and histone acetylation in cell lines representative of TCL and LGLL, as well as primary LGLL patient PBMC samples. In addition, we performed extensive in vivo modeling using murine xenografts of CTCL, including repeated dose toxicity, biodistribution, efficacy, and survival studies. Cytotoxicity assays demonstrated superior/comparable activity of NanoRomi (IC50: 1.1-2.3 nM) compared to free Romi (IC50: 4.8-10.6 nM) across all PTCL and LGLL cell lines studied, while in primary LGLL samples, NanoRomi exhibited superior cytotoxicity (2-fold) compared to Romi. WB analysis showed that NanoRomi induced apoptosis and increased acetylation of histone H3 and H4 in a time and concentration-dependent manner in cell lines representing CTCL, ALK+-ALCL, and LGLL. Repeat dose toxicity studies in CTCL xenografts confirmed that the overall tolerability of NanoRomi was substantially better than Romi. Tracking studies with a fluorescent dye (DiO) in the NanoRomi demonstrated preferential localization of NanoRomi in tumors of mice compared to the normal organs after 6 hours of drug administration. NanoRomi exhibited superior efficacy in the murine CTCL xenograft models, including a significant improvement in overall survival compared to Romi. Collectively, these data show that NanoRomi exhibits markedly superior pharmacokinetics, tolerability, and efficacy in models of TCL. We anticipate that the improved activity and tolerability of NanoRomi relate to the altered pharmacologic profile and superior bioavailability of the drug, which optimizes the effects of the drug for its influence on epigenetic biology. This unique platform offers the prospect of improving the tolerability and efficacy of epigenetic treatment strategies in these challenging diseases. Citation Format: Ipsita Pal, Anuradha Illendula, Andrea Joyner, Tess M. Deddens, Deepthi P. Damera, Todd E. Fox, Marya E. Dunlap-Brown, Kallesh D. Jayappa, Thomas P. Loughran, David J. Feith, Owen A. O'Connor. Preclinical development of a novel Romidepsin nanoparticle for the treatment of T-Cell lymphoid malignancies [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 3201.

HBI-8000 improves heart failure with preserved ejection fraction via the TGF-β1/MAPK signalling pathway.

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of total heart failure patients and is characterized by peripheral circulation, cardiac remodelling and comorbidities (such as advanced age, obesity, hypertension and diabetes) with limited treatment options. Chidamide (HBI-8000) is a domestically produced benzamide-based histone deacetylase isoform-selective inhibitor used for the treatment of relapsed refractory peripheral T-cell lymphomas. Based on our invivo studies, we propose that HBI-8000 exerts its therapeutic effects by inhibiting myocardial fibrosis and myocardial hypertrophy in HFpEF patients. At the cellular level, we found that HBI-8000 inhibits AngII-induced proliferation and activation of CFs and downregulates the expression of fibrosis-related factors. In addition, we observed that the HFpEF group and AngII stimulation significantly increased the expression of TGF-β1 as well as phosphorylated p38MAPK, JNK and ERK, whereas the expression of the above factors was significantly reduced after HBI-8000 treatment. Activation of the TGF-β1/MAPK pathway promotes the development of fibrotic remodelling, and pretreatment with SB203580 (p38MAPK inhibitor) reverses this pathological change. In conclusion, our data suggest that HBI-8000 inhibits fibrosis by modulating the TGF-β1/MAPK pathway thereby improving HFpEF. Therefore, HBI-8000 may become a new hope for the treatment of HFpEF patients.

The effect of liver dysfunction on the pharmacokinetic disposition of belinostat and its five metabolites in patients with advanced cancers.

Belinostat was approved in 2014 for the treatment of relapsed or refractory peripheral T-cell lymphoma, however, there was insufficient data to recommend a dose in patients with moderate to severe hepatic impairment. The purpose of this analysis was to characterize the pharmacokinetic disposition of belinostat and its five metabolites in patients with advanced cancers and varying degrees of liver dysfunction. A population pharmacokinetic model was therefore developed to describe the parent-metabolite system. The final model was then implemented to assess the effect of liver impairment on each metabolic pathway of belinostat. It was determined that significant pharmacokinetic differences could only be demonstrated in patients with severe hepatic impairment. The final model estimated a 35%-47% reduction in metabolic clearance attributed to UGT1A1/2B7 glucuronidation, CYP2A6/3A4/2C9 metabolism, and β-oxidation. These hepatic impairment effects reduced between-subject variability by only 5%-8% for their respective parameter, with a large amount of remaining unexplained variability. With further validation, this model can be leveraged to assess the need for dose adjustments in this patient population.

Clinical and Real-World Effectiveness of Mogamulizumab: A Narrative Review.

Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.

Autologous stem cell transplant for refractory and relapsed peripheral T-cell lymphoma: a retrospective study in China.

Objective To evaluate the efficacy and prognostic factors of high-dose therapy/autologous stem cell transplantation (HDT/ASCT) in treating refractory and relapsed peripheral T-cell lymphoma (R/R PTCL). Methods We included medical records from 48 R/R PTCL patients treated with HDT/ASCT at the Beijing Cancer Hospital from January 2003 to December 2021, and these patients were followed up. Results We followed up with patients for a median of 71.0 months (interquartile range 48.8-124.4 months). The progression-free survival (PFS) at five years was 43.4%, and the five-year overall survival (OS) was 54.7. The five-year PFS and subgroups were as follows: 14 patients with anaplastic large-cell lymphoma (57.1%, 62.9%), 14 patients with NK/T-cell lymphoma (NKTCL) (28.6%, 28.6%), nine with angioimmunoblastic T-cell lymphoma (44.4%, 51.9%), and 11 with PTCL not otherwise specified (41.6%, 80.8%). Univariate analysis revealed that females had a better PFS than males (hazard ratio [HR] = 0.301, 95% confidence interval [CI] 0.091-0.996, P = 0.049); the NKTCL type had worse OS than the non-NKTCL type (HR = 0.292, 95% CI 0.122-0.698, P = 0.006); the patients with the relapsed disease did better than those with refractory disease (HR for PFS: 0.161, 95% CI 0.072-0.357, P < 0.001; HR for OS: 0.171, 95% CI 0.066-0.444, P < 0.001). The PIT score was significantly better for T-cell lymphoma with score = 0 than for score ≥ 1 group (HR for PFS: 0.261, 95% CI 0.109-0.625, P = 0.003; HR for OS: 0.305, 95% CI 0.111-0.842, P = 0.022). The pre-transplantation disease status also influences survival. Patients who achieved complete response (CR) did better (HR for PFS: 0.104, 95% CI 0.044-0.247, P < 0.001; HR for OS: 0.139, 95% CI 0.050-0.383, P < 0.001). Pre-transplantation status was an independent influencing factor associated with PFS and OS (better survival in those achieving CR) (HR for PFS: 0.126, 95% CI 0.030-0.530, P = 0.005; HR for OS: 0.154, 95% CI 0.040-0.603, P = 0.007); the pathological classification independently influenced OS (better in the those with non-NKTCL) (HR = 0.210, 95% CI 0.081-0.549, P = 0.001). CR, with a PIT score of 0 (n = 17), was associated with more prolonged PFS. None of the 48 patients experienced HDT/ASCT-related deaths. Conclusion HDT/ASCT as a salvage therapy for R/R PTCL patients can partially improve outcomes with a favorable safety profile. Prospective, randomized, and controlled studies are necessary to validate the value of HDT/ASCT for patients with diverse pathological subtypes and pre-transplantation states.

Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study

Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. Dizal Pharmaceutical.

Retrospective Study of Allogeneic Hematopoietic Stem Cell Transplantation for Relapse or Refractory Peripheral T-Cell Lymphoma at Toranomon Hospital and Toranomon Hospital Kajigaya

[Background] Relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) is known to have a poor prognosis. Although new medications have been introduced in recent years, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for R/R PTCL. We review the results of allo-HSCT for PTCL at our institution. [Methods] We performed a retrospective analysis of R/R PTCL patients who underwent first allo-HSCT at our hospital from February 2011 and April 2023. The primary endpoint was OS, which was defined as the time from allo-HSCT to death from any cause or the last follow-up. The secondary endpoints included progression-free survival (PFS), relapse/progression incidence (RI) and non- relapse mortality (NRM). PFS was defined as the time from allo-HSCT to relapse/progression, death, or the last follow-up. OS and PFS were estimated by the Kaplan-Meier method and multivariate Cox proportional hazard models. The cumulative incidence of relapse and NRM were investigated with a competing risk analysis using Gray's test and multivariable Fine and Gray competing risk regression. [Results] During the study period, a total of 44 patients received first allo-HSCT for PTCL (ALK positive ALCL: 2, ALK negative ALCL: 2, AITL: 10, PTCL-NOS: 21, CTCL: 7, HSTL: 2). The median follow-up months of survivors was 51.6 (range, 2.6-141.6). The median age of patients at transplantation was 50 years (range, 17-70). Clinical stage I/II at diagnosis was 10 cases, and clinical stage III/IV was 34 cases. Prognostic Index for PTCL(PIT) was score 1 in 20 cases, score 2 in 20 cases and score 3 in 3 cases. Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) ≧ 2 was 21 cases. Performance Status (PS) 0-1 was 32 cases and PS 2-4 was 12 cases. Primary induction failure (PIF) was 28 cases and relapse after first remission (REL) was 16 cases, including 5 cases of relapse after autologous stem cell transplantation. Median number of chemotherapy regimens received before allo-HSCT was 3 (range, 1-8). Clinical stage at transplantation was CR/PR in 23 patients and SD/PD in 21 patients.The majority, thirty-two had received unrelated cord blood transplantation (CBT), six did unrelated bone marrow transplantation (uBMT), and 6 did related peripheral blood stem cell transplantation (rPBSCT). Thirty-two patients received myeloablative conditioning (MAC), eighteen of which included total body irradiation (TBI) and 15 of which included busulfan (BU). Twelve patients received reduced-intensity conditioning (RIC) . Regarding the primary endpoint, the 4-year OS after allo-HSCT was 53.3%. The 4-year PFS, RI and NRM were 50.4%, 20.7% and 28.8%, respectively. The 4-year OS of CBT, uBMT and rPBSCT patients was 55.2%, 66.7% and 33.3%, respectively. The 4-year OS of REL and PIF patients was 79.1% and 39.5%, respectively (p&amp;lt;0.01). The 4-year OS of MAC and RIC was 49.5% and 64.3%, respectively (p=0.58). The 4-year OS of patients with TBI was superior to patients without TBI (71.1% vs 40.3%, p=0.05). The 4-year OS of CR/PR patients at transplant was superior to SD/PD patients (67.1% vs. 42.9%, p=0.05). In the univariate analysis, PS 0-1, HCT-CI 0-1, REL, CR/PR patients at transplant, patients with TBI and patients without BU were favorable prognostic factors. In the multivariable analysis, REL was associated with better OS (p=0.01, HR 0.16; 95% CI: 0.04-0.65). Except for 3 patients who died from transplant complications before engraftment, 41 patients achieved neutrophil engraftment, with a median engraftment date of 19 days (range, 11-31 days) after transplantation. Twenty-seven patients had acute GVHD (Grade I: 3, Grade II: 13, Grade III: 8, Grade IV: 3), and 11 patients had chronic GVHD. Eleven patients relapsed after transplant, and the median time from transplant to relapse was 26.3 months (range, 0.6-87.1 months). Three patients survived at the last follow up, and the median follow-up time of survivors from relapse was 430 days (range, 12-1301). [Conclusion] Our data indicated good results of allo-HSCT for R/R PTCL, and significantly better in relapse after first remission patients.

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 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.

Transient CDK9 Inhibition with AZD4573 Effectively Induces Apoptosis in Burkitt Lymphoma As a Monotherapy in Pre-Clinical Models

Burkitt Lymphoma (BL) accounts for almost two thirds of all B-cell non-Hodgkin lymphoma cases in children and adolescents. It may affect the jaw, bones of the face, bowel, kidney, ovaries and in some cases spread to the central nervous system. Nearly all types of BL are characterized by c-MYC gene translocation of chromosome 8 with immunoglobulin genes at chromosome 2, 14 or 22 resulting in high levels of the transcription factor. Recently, MCL-1 was shown to be overexpressed in BL and is a critical survival factor in pre-clinical BL models using genetic and chemical approaches. CDK9, a serine/threonine kinase, regulates transcription elongation through phosphorylation of RNA polymerase II at serine 2 (pSer2-RNAPII). AZD4573 is a highly potent and selective CDK9 inhibitor that results in downregulation of short-lived transcripts and labile proteins such as c-MYC and key survival proteins including MCL-1 and BFL-1, resulting in apoptosis in several hematological malignancies (Cidado et al. 2020 &amp; Boiko et al. 2021) We selected several preclinical BL models to assess the rapid apoptogenic potential of AZD4573 in vitro and in vivo. To measure apoptosis, we evaluated cleaved caspase-3 (CC3) induction following acute treatment (6h) using Caspase-Glo 3/7. Using this assay, we found that 3 BL models were sensitive to CDK9 inhibition (EC50 &amp;lt; 100nM; max. CC3 &amp;gt; 50%) and 2 were resistant (EC50 &amp;gt; 100nM; max. CC3 &amp;lt; 50%). Treatment with AZD4573 in these sensitive BL cell line models decreased pSer2-RNAPII, and downregulation of MCL-1 and c-MYC within 6 hours. In AZD4573 resistant lines we observed relatively higher levels of anti-apoptotic proteins BCL2 and BCL-xL, compared to the sensitive cell lines. These increased levels potentially lead to the decreased sensitivity to AZD4573, which does not reduce levels of BCL-2 and BCL-xL due to their longer half-life. Using CRISPR genetic knockouts we demonstrate that BL cell lines are dependent on c-MYC and MCL-1 and that loss of these protein decreases caspase induction after AZD4573 treatment, highlighting the importance of these proteins in driving the efficacy of AZD4573. In vivo AZD4573 dosed on a once weekly schedule resulted in tumor growth inhibition in aggressive BL cell line xenografts Namalwa and Ramos (40-60%) and decreased pSer2-RNAPII, MCL-1 and c-MYC and increased CC3 8 hours after treatment. AZD4573 is currently in a phase 2 study (NCT05140382) to assess the efficacy, safety, and PK of AZD4573 in patients with relapsed or refractory Peripheral T-cell lymphomas (pTCL). Our findings demonstrate that targeting CDK9 with AZD4573 can effectively induce apoptosis in pre-clinical BL models and could be an effective therapy for BL patients.

Efficacy and Safety of Valemetostat Monotherapy in Patients with Relapsed or Refractory Peripheral T-Cell Lymphomas: Primary Results of the Phase 2 VALENTINE-PTCL01 Study

Introduction: Peripheral T-cell lymphoma (PTCL) is an aggressive non-Hodgkin lymphoma (NHL), with limited available treatment options for patients (pts) with relapsed or refractory (R/R) disease. Valemetostat tosylate (valemetostat) is a novel and potent dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, which is approved in Japan for the treatment of R/R adult T-cell leukemia/lymphoma (ATLL). Here, we report primary results for pts with R/R PTCL treated with valemetostat in the open-label, single-arm, global, phase 2 VALENTINE-PTCL01 study (DS3201-A-U202; NCT04703192). Methods: Pts were ≥ 18 years of age, had a confirmed diagnosis of PTCL, had R/R disease after ≥ 1 prior line of systemic therapy, and pts with anaplastic large cell lymphoma (ALCL) had received prior brentuximab vedotin treatment. Pts received oral valemetostat 200 mg/day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR), assessed by blinded independent central review of PTCL following computed tomography (CT)-based response assessment according to Lugano 2014 criteria. Secondary efficacy endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Positron emission tomography (PET)-CT-based response assessment by Lugano 2014 criteria was an exploratory endpoint. Efficacy analyses included all pts who received ≥ 1 dose of valemetostat and had an eligible PTCL subtype confirmed by central hematopathology review; safety analyses included all pts who received ≥ 1 dose of valemetostat. Results: A total of 133 pts with R/R PTCL were enrolled and received ≥ 1 dose of valemetostat. Pts had a median age of 69 years (range 22-85) and 91 pts (68.4%) were male. Pts had received a median of 2 prior lines of therapy (range 1-12) and 35 pts (26.3%) received prior hematopoietic cell transplant (HCT; autologous, n = 32; allogeneic, n = 5). PTCL subtype eligibility was confirmed in 119 pts: 42 pts (31.6%) had angioimmunoblastic T-cell lymphoma (AITL), 41 (30.8%) had PTCL, not otherwise specified (PTCL, NOS), 9 (6.8%) had ALCL (7 [5.3%] ALK-negative and 2 [1.5%] ALK-positive), 8 (6.0%) had nodal PTCL with T follicular helper cell phenotype, and 19 (14.3%) had other PTCL subtypes. As of data cutoff (May 5, 2023), 32 pts (24.1%) were still receiving treatment; reasons for treatment discontinuation included progressive or relapsed disease in 46 pts (34.6%), clinical progression in 19 pts (14.3%), adverse event in 13 pts (9.8%), and 12 pts (9.0%) discontinued study drug to proceed with allogeneic HCT. Median treatment duration was 18 weeks (range 0.3-93.4) and median duration of follow-up was 10.5 months (range 0.2-21.5). Among 119 efficacy-evaluable pts, the CT-based ORR was 43.7% (n = 52) (95% confidence interval [CI], 34.6-53.1), including 17 pts (14.3%) achieving CR and 35 pts (29.4%) achieving PR as best overall response. Median DOR was 11.9 months (95% CI, 7.8-not evaluable [NE]) and median time to response was 8.1 weeks (range 5-37). ORR by PTCL subtype ranged from 31.7% for PTCL, NOS to 54.8% for AITL (Table 1). Using PET-CT-based response assessment, ORR was 52.1% (n = 62) (95% CI, 42.8-61.3), including 32 pts (26.9%) with a complete metabolic response. Median CT-based PFS was 5.5 months (95% CI, 3.5-8.3) and median OS was 17.0 months (95% CI, 13.5-NE). Of 133 pts in the safety analysis set, 128 pts (96.2%) experienced ≥ 1 treatment-emergent adverse event (TEAE) of any grade, 77 pts (57.9%) experienced grade ≥ 3 TEAEs, and 53 pts (39.8%) experienced serious adverse events. The most common all grade and grade ≥ 3 TEAE was thrombocytopenia (Table 2). Overall, 13 pts (9.8%) experienced a TEAE that led to treatment discontinuation, 21 pts (15.8%) had a TEAE that led to dose reduction, and 66 pts (49.6%) had a TEAE that led to dose interruption. Conclusions: Valemetostat demonstrated a high ORR of 43.7% with durable responses (median DOR of 11.9 months) in pts with R/R PTCL, and responses were observed across all PTCL subtypes. A valemetostat dose of 200 mg/day was tolerable; safety analysis showed that the most common TEAEs were cytopenias. These primary results from the VALENTINE-PTCL01 study suggest that valemetostat provides a clinically meaningful benefit for pts with R/R PTCL.

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.

Updated Results of a Prospective Study: Rituximab and Lenalidomide Plus Chidamide (RLC) for Patients with Relapsed/Refractory Angioimmunoblastic T-Cell Lymphoma

Introduction Angioimmunoblastic T-cell lymphoma (AITL) is the second most common subtype of peripheral T-cell lymphoma (PTCL). The therapeutic effect of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), the most common first-line chemotherapy regimen, is not satisfactory, and most patients experience relapse or disease progression. The 5-year progression-free survival (PFS) of AITL is 13%-23%, and 5-year overall survival (OS) is 33%-36%. The benzamide histone deacetylase inhibitor (HDACi) Chidamide and lenalidomide (a second-generation immunomodulatory compound) are both approved for the treatment of relapsed or refractory PTCL in China. About 70%-100% of the AITL patients have EBV infection, which may cause abnormal immune functions in hosts. EBV infects immunocytes such as B cells, T cells, and natural killer cells, and it impairs immune functions that can clear neoplastic cells from the body. Rituximab may eradicate EBV-B cells and activated B cells and may prevent the progression to AITL. When combined with rituximab, lenalidomide augmented antibody-dependent cell-mediated cytotoxicity by enhancing NK cells, which overcomes rituximab resistance in lymphoma patients. In this prospective phase II study, the efficacy and safety of a new regimen consisting of rituximab, lenalidomide and chidamide has been evaluated in relapsed/refractory AITL patients. We have reported the preliminary results (2022 ASH, poster 1600), and now we update the data of this study. Methods Patients with relapsed/refractory AITL after at least first-line chemotherapy were treated with up to 6 cycles of a rituximab and lenalidomide plus chidamide (RLC) regimen every 3 weeks. The initial dose of each drug has been reported. The primary endpoint of the study was PFS. The secondary endpoints included overall response rate (ORR), OS, and adverse events (AEs). Results Between Aug 2019 and May 2023, 24 patients with relapsed/refractory AITL were enrolled. The characteristics of these patients are listed in table 1. On enrollment, 16 (66.7%) patients had received 1st-line chemotherapy, 7 (29.1%) patients had received 2nd-line chemotherapy, and 1 (4.2%) patient had received 3rd-line chemotherapy. The median age was 63 years (range 43-78) and 9 (37.5%) patients were female. Fifteen (62.5%) patients had B symptoms, including weight loss in 3 (12.5%) cases, night sweat in 1 (4.2%) case and fever in 11 (45.8%) cases. Sixteen (66.7%) patients had elevated serum lactate dehydrogenase (LDH), and 21 (87.5%) patients had IPI score≥2. All patients had completed RLC treatment for at least 1 cycle and underwent imaging assessment. The ORR was 75% (18/24) with a complete remission (CR) rate of 20.8% (5/24), and 13 (54.2%) patients achieved partial remission (PR). While 1 (4.2%) patient achieved stable disease (SD) and 5 (20.8%) patients achieved progressive disease (PD). Two patients received autologous hematopoietic stem cell transplantation as consolidation treatment after achieving CR from RLC chemotherapy. With a median follow-up of 9.7 months, 9 patients had died. The median PFS was 10.8 months (95% confidence interval &amp;lt;CI&amp;gt;, 9.0 to 12.6 months), but the median OS was not reached. No patient presented with Grade 5 AE. The most frequent all-grade hematological toxicity included leucopenia (35.7%, 5/14), followed by anemia (21.4%, 3/14) and thrombocytopenia (41.7%, 10/24). Other common toxicities included infusion reaction (16.7%, 4/24), skin rash (20.8%, 5/24), pulmonary pneumonia (41.7%, 10/24), and nausea (12.5%, 3/24). Dose reduction was performed in 8 patients. The exploratory analysis of possible prognostic factors by mass spectrum flow are undergoing. Conclusions The updated results of this prospective study confirmed the good response rate and manageable toxicity of rituximab and lenalidomide plus chidamide (RLC) regimen. This combination may be a promising regimen in patients with relapsed/refractory AITL.

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.

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.

Phase I dose escalation and expansion study of golidocitinib, a highly selective JAK1 inhibitor, in relapsed or refractory peripheral T-cell lymphomas

Relapsed or refractory peripheral T-cell lymphomas (r/r PTCLs) are a group of rare and aggressive diseases that lack effective therapies. Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is reported to be associated with PTCLs. Golidocitinib is an oral, potent JAK1 selective inhibitor evaluated in a phase I/II multinational study in patients with r/r PTCLs. Patients with r/r PTCLs were eligible. The primary objectives were to assess safety and tolerability of golidocitinib and to define its recommended phase II dose (RP2D). The secondary objectives were to evaluate its antitumor activity and pharmacokinetics (PK). A total of 51 patients were enrolled and received golidocitinib treatment at 150 or 250 mg once daily (QD). The median prior lines of therapies were 2 (range: 1-8). Golidocitinib was tolerated at both doses tested, while a higher incidence of serious adverse events and dose modifications at 250 mg were observed. The most common grade ≥3 drug-related treatment-emergent adverse events were neutropenia (27.5%) and thrombocytopenia (11.8%). An objective response rate of 39.2% and a complete response rate of 21.6% were observed. With median follow-up time of 14.7 and 15.9 months, the median duration of response (DoR) and progression-free survival were 8.0 and 3.3 months, respectively. Based on these data, 150 mg QD was defined as the RP2D. Golidocitinib demonstrated a favorable PK profile as an oral agent. Biomarker analysis suggested a potential correlation between JAK/STAT pathway aberrations and clinical activity of golidocitinib. In this phase I study, golidocitinib demonstrated an acceptable safety profile and encouraging antitumor efficacy in heavily pretreated patients with r/r PTCLs. These results support the initiation of the multinational pivotal study in patients with r/r PTCLs.

Phase 2 study of HDAC inhibitor tucidinostat in combination with anti-PD-1 antibody in patients with locally advanced or metastatic urothelial carcinoma.

e16563 Background: Tucidinostat (also known as chidamide), a novel histone deacetylase (HDAC) inhibitor, has been approved for treatment of patients (pts) with relapsed or refractory peripheral T-cell lymphoma and advanced hormone receptor-positive breast cancer in China. Tislelizumab (a PD-1 checkpoint inhibitor) is currently approved for pts with PD-L1-high locally advanced or metastatic urothelial carcinoma (UC) who progressed during/following platinum-containing therapy in China. However, the response rate of tislelizumab as monotherapy is limited in UC. The aim of this study was to evaluate the efficacy and safety of tucidinostat combined with tislelizumab in pts with locally advanced or metastatic UC. Methods: This study is an open-label, single-center, phase Ⅱ trial. Patients who previously failed systemic platinum-based chemotherapy with UC were included, regardless of PD-L1 status. Eligible pts received 30 mg oral tucidinostat twice weekly (BIW) in combination with 200 mg tislelizumab by intravenous drip every three weeks (Q3W). This is a Simon's two-stage design. All pts were treated until progression or unacceptable toxicity in two years. The primary endpoint was objective response rate (ORR). The secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), the safety and tolerability. Results: From Jan. 2021 to Sep. 2022, 26 pts were enrolled (median age 62 y, range 31-74y), of whom 24 were evaluable for response per RECIST 1.1 criteria. One pt was lost to follow-up and one withdrew the group due to sudden cerebral infarction. Complete response (CR) was observed in 2 pts, while partial response (PR) was observed in 8 pts, with an ORR of 41.7% (10/24). The DCR was 62.5%. The median PFS was 4.6 months. Most adverse events (AEs) were grade 1 or 2. The most common grade 3 AEs were neutropenia 11.5%, thrombocytopenia 11.5%, leukopenia 7.7%, anemia 7.7%, anorexia 7.7%, creatinine increased 3.8%. One pt experienced grade 4 immuno-pneumonia was permanently discontinued. One pt was on maintenance therapy of tucidinostat without immunotherapy because of interstitial pneumonia. Conclusions: The preliminary data indicate that tucidinostat combined with tislelizumab might be a potentially effective regimen with a manageable safety profile in UC. The study remains ongoing and updated results will be presented later. Clinical trial information: NCT04562311 .

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

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