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IRF4 AND SERBP1 EXPRESSION ARE ASSOCIATED WITH POOR RESPONSES TO GUADECITABINE (SGI-110) THERAPY IN PERIPHERAL T CELL LYMPHOMA.

2026-08-14T01:44:45Z

Title: IRF4 AND SERBP1 EXPRESSION ARE ASSOCIATED WITH POOR RESPONSES TO GUADECITABINE (SGI-110) THERAPY IN PERIPHERAL T CELL LYMPHOMA. Authors: Behrouzfar K.; Abeyakoon C.; Waltham M.; Dorwal P.; Maher B.; Sabouri-Thompson Z.; Scull K.; Brasacchio D.; Gasiorowski R.; Shortt J.; Yeh P. Abstract: Background Peripheral T cell lymphomas (PTCL) are aggressive non-Hodgkin lymphomas with a 5-year survival < 50%, and a lack of effective salvage therapies. Although hypomethylating agents (HMA) offer a potential novel treatment for PTCL, less than half of these patients respond to therapy. This highlights the necessity of developing predictive approach to inform selection of patients for HMA therapy. Aims We aimed to identify gene expression profiles and candidate genes expressed in PTCL predicting response to HMA therapy. Methods We performed RNA sequencing on Formalin Fixed Paraffin Embedded (FFPE) samples (n=11) that were previously collected from lymph node (n=9) and skin (n=2) of PTCL patients before being treated with Guadecitabine in single arm phase II clinical trial (ACTRN12618000028202). Patient characteristics distribution is outlined in the table 1. We leveraged differential gene expression analysis workflow in addition to Gene Set Enrichment Analysis (GSEA) to characterise gene expression profiles of samples from Guadecitabine-treated patients dichotomised by the best clinical response. Patients with Progressive Disease (PD) were classified as 'non-responders', while those with Stable Disease beyond 2 cycles (SD), Partial Response (PR) or Complete Response (CR) were classified as 'responders'. We applied the Leave-One-Out Cross-Validation (LOOCV) method and mirrorCheck to identify genes that are insensitive to outlier and reciprocal contrast effects. (Table presented) Results Our analysis revealed consistent and reliable expression of IRF4 and SERBP1 in non-responders versus responders to Guadecitabine (Figure 1. A & B). Moreover, GSEA demonstrated the greater enrichment of gene sets associated with cell cycle and cell proliferation in non-responders (Figure 1. C). The gene sets that are functionally related to methylation were also significantly enriched in non-responders compared to responders in this cohort. Summary/Conclusion We identified IRF4 and SERBP1 as candidate genes predicting resistance to HMA therapy in PTCL. Their elevated expression in non-responders, together with the enrichment of gene sets related to cell proliferation and methylation, suggests their potential role in lymphoma progression and HMA sensitivity. These findings warrant validation in larger independent cohorts and functional studies to determine whether IRF4 and SERBP1 may serve as predictive biomarkers for HMA resistance and to clarify their mechanistic contribution to PTCL pathobiology. (Figure presented)

EVALUATION OF PET-CT METRICS AND PHARMACOKINETICS IN ADULTS RECEIVING TISLELIZUMAB FOR RELAPSED/REFRACTORY CLASSICAL HODGKIN LYMPHOMA: ANCILLARY ANALYSES OF LYSA PHASE 2 TIRHOL STUDY BGB-A317-210.

2026-08-14T01:44:45Z

Title: EVALUATION OF PET-CT METRICS AND PHARMACOKINETICS IN ADULTS RECEIVING TISLELIZUMAB FOR RELAPSED/REFRACTORY CLASSICAL HODGKIN LYMPHOMA: ANCILLARY ANALYSES OF LYSA PHASE 2 TIRHOL STUDY BGB-A317-210. Authors: Ghesquieres H.; Bouabdallah K.; Kanoun S.; Andre M.; Quittet P.; Borel C.; Bastard A.S.; Gilbertson M.; Le Bras F.; Thieblemont C.; Moisdon B.D.; Touati M.; Feugier P.; Renaud L.; Morineau N.; Gastinne T.; Chaillol I.; Ramchandren R.; Shah H.; Modi D.; Allewelt H.; Fustier P.; Liu X.; Zhang J.; Delarue R.; Morschhauser F.; Rossi C. Abstract: Background Conventional methods using PET-CT to assess lymphoma response are suboptimal in patients (pts) treated with PD1 inhibitors; specialized criteria are required to prevent premature treatment discontinuation due to inflammation unrelated to disease progression. In the LYSA phase 2 BGB-A317-210 study (NCT04318080), 45 pts with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) were treated with tislelizumab every 3 weeks until progressive disease (PD), unacceptable toxicity, or study withdrawal; disease response was assessed by investigator every 12 weeks according to Lugano 2014 PET-CT classification. At final analysis, the overall response rate (ORR), the primary endpoint of TIRHOL, was 66.7% (95%CI, 51%-80%), and the complete response rate was 31%. PK profiles were comparable between BGB-A317-210 and the prior Chinese study BGB-A317-203. Aims For this correlative analysis, PET-CT imaging in pts in the TIRHOL study was evaluated post-hoc by a central, independent reviewer. Methods Relationships were assessed between baseline PET-CT metrics (TMTV4, TLG4, Dmax4, SUVmean, and SUVmax) and response assessments, progression-free (PFS), and overall survival (OS). The longitudinal evolution of TMTV4 and SUV during tislelizumab therapy was also examined. Tislelizumab PK profiles (cycle 1 post-dose and cycle 2 pre-dose concentrations) were evaluated against baseline clinical and PET-CT characteristics. Results Baseline and follow-up PET-CT images were available for post-hoc central review for 37 of the 45 pts in TIRHOL. ORR was 70%, with complete metabolic response (CMR) observed in 15 pts (40%) and partial metabolic response (PMR) in 11 (30%); remaining pts had no metabolic response (NMR; stable disease or PD; n=10, [27%]), or were not evaluated (n=1, [3%]). At the first metabolic evaluation at Week 12, 10 pts had CMR (27%), 13 had PMR (35%), 13 had NMR (35%) and 1 (3%) was not evaluated. Pts with best metabolic response of CMR, PMR and NMR had 1-year PFS rates of 60%, 26%, and 8%, and 1-year OS rates of 100%, 100%, and 77%, respectively. Median baseline PET-CT metrics were comparable across Week 12 and best metabolic response categories and were comparable between pts with PFS or OS events and those who remained event-free. Longitudinal evaluations of TMTV4 and SUV showed a rapid decrease of values at first evaluation for pts with CMR and PMR at Week 12. The patterns of TMTV4 and SUV variations during tislelizumab treatment differed between pts with best metabolic response of CMR, PMR, and NMR. No differences in PK results were observed based on key baseline categorical variables (sex, age, B-symptoms, cohort 1/2, Ann Arbor stage, bulk, refractory vs relapse, IPS score, TMTV4, albumin level). Summary/Conclusion Central review of PET-CT imaging confirmed that tislelizumab is an effective therapeutic option for pts with R/R cHL, and efficacy may have been underestimated in the TIRHOL study. Tislelizumab PK and efficacy outcomes did not differ between baseline PET-CT metrics. OS was lower in pts with NMR at Week 12 compared with pts who had CMR or PMR. Analyses of centrally reviewed PET-CT imaging demonstrated a trend for underestimation of local response assessments, and therefore in ORR (70% vs. 66.7%) and CMR rate (40% vs. 31%), likely due to the presence of non-lymphomatous inflammatory lesions. Variations in PET-CT parameters during anti-PD1 therapy should be interpreted with caution to avoid premature treatment discontinuation.

PROPOSED DEFINITION FOR 'PRIMARY REFRACTORY' DISEASE IN NODAL PERIPHERAL T-CELL LYMPHOMA: AN AUSTRALASIAN-CANADIAN COLLABORATIVE STUDY.

2026-08-14T01:44:45Z

Title: PROPOSED DEFINITION FOR 'PRIMARY REFRACTORY' DISEASE IN NODAL PERIPHERAL T-CELL LYMPHOMA: AN AUSTRALASIAN-CANADIAN COLLABORATIVE STUDY. Authors: Abeyakoon C.; Wellard C.; Chung E.; Hodgson D.; Rodin D.; Prica A.; Aoki T.; Vijenthira A.; Opat S.; Wood E.; McQuilten Z.; Hawkes E.; Crump M.; Gregory G.; Kuruvilla J. Abstract: Background There is no universally accepted definition of 'primary refractory' disease in nodal peripheral T-cell lymphoma (nPTCL), with heterogeneous criteria applied across registry analyses and clinical studies. Pivotal phase II trials of novel agents in relapsed/refractory nPTCL have not reported outcomes specific to this subgroup, limiting interpretation and cross-study comparisons. Aims To determine the optimal time-based definition of 'primary refractory' disease in nPTCL by evaluating survival outcomes according to time-to-relapse (TTR) post primary treatment (1L). Methods We performed a retrospective analysis of the Australasian Lymphoma and Related Diseases Registry (LaRDR; Jan 2016-Dec 2023) and the Princess Margaret Cancer Centre lymphoma database (PMH; Nov 2011-Mar 2024). Adults (>18 years) treated with 1L therapy for nPTCL were included, comprising PTCL-not otherwise specified, T follicular helper (TFH)-type lymphomas (angioimmunoblastic T-cell lymphoma, PTCL with TFH phenotype, follicular T-helper lymphoma), and anaplastic large cell lymphoma. Patients (pts) were stratified by TTR from end of 1L therapy: stable/progressive disease (SD/PD) after 1L; relapse <3months (m), 3-6m, 6-12m, and >12m. Progression-free survival-2 (PFS2) and overall survival-2 (OS2) were calculated from first progression to second progression or death, and to death from any cause, respectively. Results A total of 451 pts were included (LaRDR 285; PMH 166). 1L therapy was typically CHOP-based. Imaging responses to 1L were available in 319 pts (PET/CT 282, CT 37). 358/451 experienced SD/PD to or relapse after 1L: SD/PD (n=100), <3m (n=49), 3-6m (n=26), 6-12m (n=50), and >12m (n=133). Median follow-up was 43m (95% CI 39-48). Baseline characteristics, median PFS and OS by TTR are shown in Table 1. Pts with SD/PD or relapse <6m from 1L had significantly inferior outcomes compared with those relapsing >6m, clearly separating two prognostic groups (Table 1). In multivariate analysis, pts with SD/PD or relapse <6m from 1L had significantly inferior PFS (adjusted hazard ratio [aHR] 2.1 (95%CI 1.5-3), p<0.001) and OS (aHR 2.8 (95%CI 1.8-4), p<0.001) when adjusted for age, nodal subtype, ECOG and gender. (Table presented). Summary/Conclusion Pts with SD/PD or relapse <6m following 1L represent a distinct high-risk group in nPTCL. We propose defining this cohort as 'primary refractory' disease. Although our pts received global standard care, external validation in international cohorts is planned. A unified definition would enable accurate risk stratification, consistent outcome reporting and improved trial design for high-risk pts. (Figure presented).

COMBINATION TREATMENT WITH NOVEL BCL2 INHIBITOR SONROTOCLAX (BGB-11417) AND ZANUBRUTINIB IN PATIENTS WITH RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA (R/R MCL): RESULTS FROM A PHASE 1/1B STUDY.

2026-08-14T01:44:44Z

Title: COMBINATION TREATMENT WITH NOVEL BCL2 INHIBITOR SONROTOCLAX (BGB-11417) AND ZANUBRUTINIB IN PATIENTS WITH RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA (R/R MCL): RESULTS FROM A PHASE 1/1B STUDY. Authors: Soumerai J.; Tam C.S.; Lasica M.; Hoffmann M.; Sanz R.G.; Schetelig J.; Munir T.; Weinkove R.; Browett P.; Barca E.G.; Mayer L.M.; Bernardelli A.; Hou J.-Z.; Cordoba R.; Wu B.; Man G.; Fang Y.; Patel S.; Vezan R.; Opat S. Abstract: Background MCL is characterized by recurrent relapse after short remission periods. Venetoclax + ibrutinib demonstrated efficacy in R/R MCL but treatments (tx) with improved tolerability and efficacy are needed. Sonrotoclax (sonro), a next-generation BCL2 inhibitor, is a more selective and pharmacologically potent BCL2 inhibitor vs venetoclax, with a shorter half-life and no drug accumulation. Zanubrutinib (zanu) is a next-generation covalent BTK inhibitor with fewer off-target adverse events vs other BTK inhibitors and is FDA approved for R/R MCL. Aims To report safety and efficacy of sonro + zanu (SZ) combination therapy in patients (pts) with R/R MCL with median follow-up of ~2 y. Methods BGB-11417-101 (NCT04277637) is an ongoing open-label, phase 1/1b dose escalation and expansion study. Eligible adults have R/R MCL and received >=1 prior therapy. Tx started with zanu lead-in (320mg once daily [QD] or 160mg twice daily) for 8-12 wk; then sonro was added. Ramp-up to sonro target dose (80, 160, 320, or 640mg QD) was used to mitigate risk of tumor lysis syndrome (TLS). Combination therapy continued until progressive disease (PD), unacceptable toxicity, or elective discontinuation after 96 wk. The primary endpoint was safety (eg, TLS; Howard criteria); secondary endpoints included overall response rate (ORR; partial response [PR] or better; Lugano 2014 criteria). Results As of Dec 6, 2025, 51 pts were enrolled in sonro dose cohorts: 80mg (n=6), 160mg (n=13), 320mg (n=27), and 640mg (n=5). Forty-six pts (90.2%) initiated SZ; as of data cutoff, 25 (49.0%) remained on tx. Median age was 68 y and 70.6% of pts were male. Pts had a median of 1 prior tx (range, 1-4; median duration of last tx, 6.0 mo [range, 0.1-65.6]); prior tx included stem cell transplant (n=15; 1 allogeneic, 14 autologous), CAR-T (n=1), and BTK inhibitor (n=4). Maximum tolerated dose was not reached; RP2D was 320mg QD. Twenty-one pts (41.2%) discontinued SZ and 6 (11.8%) discontinued zanu only. TEAEs led to discontinuation of SZ in 4 pts (7.8%) and zanu only in 2 (3.9%; diarrhea and cryptococcal meningoencephalitis); none led to discontinuation of sonro only. TEAEs led to death in 2 pts (3.9%; pneumonia; abdominal sepsis). The most common any-grade TEAEs were diarrhea (37.3%), neutropenia (33.3%), and COVID-19 (33.3%). Grade >=3 TEAEs occurred in 66.7% of pts; neutropenia (21.6%) was the most common. Serious TEAEs occurred in 41.2% of all pts; pneumonia (15.7%) was the most common. In sonro 320mg + zanu pts, the most common any-grade TEAE was diarrhea (51.9%; most grade 1-2) and grade >=3 TEAE was neutropenia (22.2%). No laboratory or clinical TLS occurred. In 51 pts across doses, ORR was 80.4%; complete response (CR) rate was 60.8%. Median time to CR was 6.4 mo (range, 1.5-32.5). With a median study follow-up of 25.5 mo (range, 0.7-51.6), 80.6% of pts who achieved CR (25/31) remain in CR. In sonro 320mg + zanu pts (median follow-up, 21.3 mo), ORR was 81.5% (22/27); CR rate was 59.3% (16/27). Median duration of response (DOR) was not reached; 30-mo DOR rate was 77.7% (95% CI, 50.2%-91.2%). Of 4 pts with prior BTK inhibitor therapy, 2 achieved PR. All 6 pts who elected to discontinue tx achieved CR and remain in complete remission (median time off tx, 9.6 mo; range, 2.9-12.1). Summary/Conclusion SZ is well tolerated with promising antitumor activity. A phase 3 registrational trial assessing sonro 320mg + zanu is ongoing (NCT06742996).