Hematological Oncology最新文献

{"title":"OUTCOMES OF PATIENTS WITH PRIMARY REFRACTORY AND EARLY RELAPSING LARGE B CELL LYMPHOMA ARE INFERIOR IN THE CD19 CAR T CELL THERAPY ERA","authors":"I. Y. Gong, M. Marinoni, M. Azab, T. Aoki, S. Bhella, C. Chen, R. Kridel, V. Kukreti, A. Prica, A. Vijenthira, C. Yang, D. Hodgson, N. Malik, D. Rodin, W. Wells, M. Crump, J. Kuruvilla","doi":"10.1002/hon.70094_311","DOIUrl":"https://doi.org/10.1002/hon.70094_311","url":null,"abstract":"<p><b>Introduction:</b> Although early relapse in relapsed/refractory (R/R) large B cell lymphoma (LBCL) is associated with worse outcomes, the definition of primary refractory disease (PRD) has varied. This study aimed to evaluate the association of time to relapse (TTR) on the trajectory of second line (2L) treatments and outcomes.</p><p><b>Methods:</b> This retrospective study included pts aged ≥ 18 with R/R LBCL at Princess Margaret Cancer Centre (2017–2024, follow-up 01/25). TTR was categorized as PRD (progression during or at end of 1L treatment or < 3 mos), early relapse within 3–12, 12–24, or ≥ 24 mos of 1L rituximab-based therapy. Univariate and multivariable Cox regression analyses assessed the association between TTR and overall survival (OS) and progression-free survival (PFS) from first (OS1, PFS1) and second progression (OS2). Covariates included age, diagnosis, rIPI, and LDH.</p><p><b>Results:</b> Of 367 pts (median age 61, 63% male) included, pts with PRD were more likely to have HGBL and GCB subtype. There were no significant differences in characteristics between relapse groups at first progression (Table 1). For 2L treatment, 86% received platinum-based salvage chemotherapy (SC), and 48% underwent ASCT. Response rates were significantly higher in TTR ≥ 24 mos (81%) compared to PRD (50%), 3–12 mos (60%), and 12–24 mos (68%) (<i>p</i> < 0.001). At median follow-up of 41 mos, 245 (67%) of pts progressed, and 154 (42%) died. The 5-y OS1 was 45%; median OS1 for PRD and early relapse (3–12 mos) was 23 and 24 months, respectively, compared to not reached for relapse ≥ 24 mos (12–24 mos 56 mos). Cox analysis showed PRD and early relapse ≤ 12 mos were associated with inferior OS1 and PFS1 (OS1: PRD aHR 3.8: 95% CI: 2.1–7.2, <i>p</i> < 0.001; 3–12 mos aHR 3.3: 1.7–6.5, <i>p</i> < 0.001), while 12–24 mos was not (aHR 1.7: 0.7–4.1, <i>p</i> = 0.25) (Figure 1). Sensitivity analysis in de novo LBCL pts did not change these findings. Of the 245 patients who progressed after 2L, 120 (49%) had PRD after 1L. PRD and early relapse were associated with refractoriness to 2L treatment (92% and 67%, vs. 50%; <i>p</i> < 0.001). The 5-y OS2 was 34% (median 14 mos). Cox analysis showed PRD and early relapse were associated with worse OS2 compared to ≥ 24 mos (PRD aHR 2.3: 1.3–4.3, <i>p</i> = 0.008; 3–12 mos aHR 2.0: 1.0–3.8, <i>p</i> = 0.043; 12–24 mos aHR 1.4: 0.6–3.5, <i>p</i> = 0.43) (Figure 2). For 3L treatment, 215 pts were considered for CAR-T (85% apheresed), and 154 (72%) were CAR-T infused. Multivariable analysis showed the combined cohort of pts with PRD/early relapse < 12 mos was associated with worse OS2 compared to relapse > 12 mos (aHR 2.2: 1.1–4.4, <i>p</i> = 0.022; mOS2 for early relapse 31 mos vs. NR for late relapse).</p><p><b>Conclusions:</b> Our study shows that early relapse, particularly pts with PRD, continues to be associated with inferior outcomes even with 3L CAR-T. The association of relapsing timing on 2L","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CIRCULATING TUMOR DNA SEQUENCING REVEALS RAPID RESPONSE KINETICS TO ANTI-PD1 BASED FIRST-LINE TREATMENT OF HODGKIN LYMPHOMA: MOLECULAR INSIGHTS FROM THE GHSG NIVAHL TRIAL","authors":"J. Heger, J. Mattlener, P. Herhaus, J. Meissner, K. Trautmann-Grill, C. Voltin, J. Schneider, J. K. Schleifenbaum, S. Heidenreich, C. Kobe, H. Kaul, W. Klapper, B. von Tresckow, P. J. Bröckelmann, S. Borchmann","doi":"10.1002/hon.70093_43","DOIUrl":"https://doi.org/10.1002/hon.70093_43","url":null,"abstract":"<p>P. J. Bröckelmann, S. Borchmann equally contributing authors.</p><p>Anti-PD1 immune checkpoint blockade (ICB) has been incorporated into first-line treatment of classic Hodgkin lymphoma (HL) in several clinical trials recently. The GHSG NIVAHL trial demonstrated high response rates to both sequential and concomitant treatment with ICB and chemotherapy (Bröckelmann, <i>JCO</i>, 2023). However, it remains unclear whether some patients might achieve long-term remission following ICB alone and how to identify them without risking treatment failure. Recently, two studies established a circulating tumor (ct)DNA-based biologic classification of HL including subtypes with an immune escape phenotype that might be particularly sensitive to ICB (Alig, <i>Nature</i>, 2024; Heger, <i>JCO</i>, 2024). Despite these advances, the role of biologic HL classifiers and ctDNA-based minimal residual disease (MRD) kinetics during anti-PD1 first-line treatment have not yet been studied.</p><p>The multicenter, randomized GHSG phase II NIVAHL trial evaluated an either sequential or concomitant combination of AVD with the anti-PD1 antibody nivolumab (N) in 109 patients with previously untreated, early-stage unfavorable HL. ctDNA sequencing was applied to plasma samples obtained at baseline, one week after treatment initiation and at all three imaging response assessments as previously described (Heger, <i>JCO</i>, 2024).</p><p>Samples were available from 69 (baseline), 23 (after 1xN-AVD or 1xN), 30 (first restaging after 2xN-AVD or 4xN), 24 (end of systemic therapy after cumulatively 4xN-AVD) and 24 (following 30 Gy IS-RT) patients, respectively. Patient characteristics of this subset were representative of the whole study cohort. Strikingly, 6/19 (31.6%) patients achieved MRD negativity following just one infusion of nivolumab. Patients with <i>Inflammatory immune escape HL</i> or <i>Virally-driven HL</i> had higher rates of MRD negativity after just one infusion of nivolumab compared with patients with <i>Oncogene-driven HL</i> (50% versus 23.1%, Figure 1A). At later timepoints, assessment of MRD allowed for the detection of complete molecular response also in patients with remaining metabolic activity by Deauville-score based PET assessment: At the end of systemic therapy, 8/24 (33.3%) patients were PET positive, while MRD indicated complete molecular remission in 24/24 (100%) of patients (Figure 1B). Importantly, with a median follow-up of 41 months, none of the 8 PET positive patients relapsed or died.</p><p>Here, we present the first study evaluating the impact of biologic HL classifiers and very early MRD kinetics in HL patients receiving ICB first-line treatment. Our results suggest that molecular risk stratification might allow to select HL patients with exceptional benefit from anti-PD1 ICB alone. In these patients, chemotherapy might be reduced or omitted in future clinical trials. At the end of systemic anti-PD1 based first-line treatment, MRD might allow fo","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_43","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LONG-TERM SURVIVAL TRENDS IN ADVANCED-STAGE MANTLE CELL LYMPHOMA: A POOLED ANALYSIS OF SIX RANDOMIZED PHASE III TRIALS FROM 1996 TO 2020","authors":"L. Jiang, M. Ladetto, O. Hermine, J. C. Kluin-Nelemans, M. Unterhalt, M. Dreyling, E. Hoster","doi":"10.1002/hon.70093_133","DOIUrl":"https://doi.org/10.1002/hon.70093_133","url":null,"abstract":"<p><b>Introduction:</b> Mantle cell lymphoma (MCL) remains a challenging disease with a poor prognosis, despite advancements in treatment strategies. Since 1996, the German Low-Grade Lymphoma Study Group (GLSG, now German Lymphoma Alliance) and the European MCL Network have conducted six landmark randomized phase III trials—GLSG1996, GLSG2000, European MCL trial 1, MCL Younger, MCL Elderly, and TRIANGLE, which have transformed the standard of care for advanced-stage MCL patients. This study aimed to evaluate survival trends in advanced-stage MCL patients over the past three decades, focusing on the impact of evolving first-line treatments.</p><p><b>Methods:</b> We performed a pooled analysis of six randomized phase III trials including treatment-naïve, advanced-stage MCL patients enrolled between 1996 and 2020. Patients were grouped into four eras (1996–2000, 2000–2004, 2004–2014, 2016–2020) based on trial enrollment periods. Overall survival (OS) was compared across eras using Kaplan-Meier methods and Cox regression models adjusted for MCL International Prognostic Index (MIPI) and treatment regimens. Additionally, we analyzed dynamic survival trends on a continuous time scale using penalized splines.</p><p><b>Results:</b> Among 2541 MCL patients, survival outcomes have improved steadily since 1996. In younger patients (< 60 or ≤ 65 and suitable for high-dose treatment), median OS significantly increased from 4.9 years (5-year OS: 49%) in 1996–2000 to 6.4 years (60%) in 2000–2004, to 13.8 years (73%) in 2004–2014 and was not yet reached (84%) in 2016–2020, with nearly doubled OS in 2004–2014 (vs. 2000–2004: MIPI-adjusted HR [aHR] = 0.56, 95% CI: 0.44–0.72, <i>p</i> < 0.0001) and 2016–2020 (vs. 2004–2014: aHR = 0.52, 0.41–0.65, <i>p</i> < 0.0001) (Figure A). In older patients (> 65 or ≥ 60 and ineligible for high-dose treatment)), median OS improved albeit to a less extent from 3.8 years (5-year OS: 40%) in 1996–2000 to 4.3 years (43%) in 2000–2004, and to 4.8 years (49%) in 2004–2014, with improved OS in 2000–2004 (vs. 1996–2000: aHR = 0.70, 0.51–0.96, <i>p</i> = 0.025) and 2004–2014 (vs. 2000–2004: aHR = 0.80, 0.64–1.02, <i>p</i> = 0.070) (Figure B). In younger patients, dynamic modeling revealed a sharp decline in mortality risk between 2000 and 2005, followed by sustained improvements (Figure C). In older patients, dynamic modeling showed a constant decrease in risk from 1996 to 2014 (aHR = 0.95, 0.93–0.97, <i>p</i> < 0.0001) (Figure D). Patients receiving the same treatment regimens had comparable OS across different eras. Adjusting for treatment regimens eliminated most survival trends, underscoring the impact of ASCT, immunochemotherapy, rituximab maintenance, high-dose cytarabine-containing regimen, and ibrutinib on survival improvements.</p><p><b>Conclusions:</b> Survival outcomes in MCL have substantially improved over the past three decades, especially in younger patients, driven largely by advancements in first-line trea","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_133","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RITUXIMAB AND EPCORITAMAB AS FIRST-LINE THERAPY FOR PATIENTS WITH HIGH-TUMOR BURDEN FOLLICULAR LYMPHOMA: FIRST RESULTS OF A MULTICENTER PHASE II TRIAL","authors":"R. Merryman, D. S. Wallace, R. Redd, H. A. Walker, R. Tringale, V. Kats, A. Sigmund, I. E. Ahn, A. Bessnow, J. R. Brown, J. L. Crombie, M. S. Davids, D. C. Fisher, C. K. Hahn, E. D. Jacobsen, C. A. Jacobson, A. I. Kim, A. S. LaCasce, O. O. Odejide, E. M. Parry, D. Qualls, C. E. Ryan, A. Sekar, S. Devata, C. Casulo, K. Maddocks, M. Murakami, P. Armand, Y. Sawalha","doi":"10.1002/hon.70094_227","DOIUrl":"https://doi.org/10.1002/hon.70094_227","url":null,"abstract":"<p>R. Merryman and D. S. Wallace equally contributing author.</p><p><b>Introduction:</b> Patients (pts) with follicular lymphoma (FL) would benefit from chemotherapy-free frontline treatments that provide high response rates, durable remissions, and a favorable safety profile. Epcoritamab (epco) is a CD3xCD20 bispecific antibody (BsAb) approved in multiply relapsed FL where it results in high overall response rates (ORRs). In other settings, debulking therapy before BsAb treatment appears to reduce the risk of cytokine release syndrome (CRS). We hypothesized that treatment with rituximab (R) for debulking before initiation of full dose epco could lower the risk of CRS and deepen responses based on its distinct mechanism of targeting CD20. Here we present the first results of a phase 2 multicenter trial (NCT05783609) of time-limited therapy with R+epco.</p><p><b>Methods:</b> Eligibility criteria include: age ≥ 18, stage II-IV, grade 1–3A FL, requirement for therapy based on modified GELF criteria, and ECOG PS 0–2. In cycle 1 (C1), pts receive 4 weekly doses of R (D −14, −7, 1, 8) and weekly subcutaneous epco on D1 (0.16 mg), D8 (0.8 mg), and D15/D22 (48 mg). Epco is dosed weekly in C2–3 and biweekly in C4–9. After 26 pts enrolled, a 3<sup>rd</sup> epco step-up dose (D15, 3 mg) was added and inpatient observation for C1D15 was no longer required. Responses are evaluated based on Lugano 2014 criteria after 2, 5, and 9 cycles.</p><p><b>Results:</b> As of 1/31/2025, 31 of 35 planned pts had enrolled. The median age was 57 (range 28–78). At study entry, 30 pts (97%) had stage III/IV, 8 (26%) bulky disease (≥ 7 cm), 7 (23%) grade 3A FL, and 17 (55%) a FLIPI score of 3–5.</p><p>Among 25 response-evaluable pts (6 pts awaiting 1st response assessment), the best ORR and complete metabolic response (CMR) rates were 100% and 92%, respectively. Rapid responses were observed (22 CMRs, 3 partial metabolic responses [PMRs] after 2 cycles of therapy). 1 PMR subsequently converted to a CMR and the other 2 pts have not yet been restaged. With a median follow-up of 6.0 months (m) (range 0–17.6), no pts have relapsed, yielding a 6 m PFS estimate of 100%.</p><p>Among 31 safety-evaluable pts, the most common adverse events (AEs) were CRS (48%; G1 39%; G2 6%, no G3+), fatigue (39%), injection site reactions (39%; G1 35%, G2 3%), and infections (39%; G1 6%, G2 23%, G3 10%). G3 infections include bacteremia, COVID-19, and lung infection. In each case, the infection resolved and the pt restarted study treatment. Other common grade 3+ AEs included neutropenia (16%) and lymphocytopenia (6%). 3 pts discontinued treatment due to an AE (persistent G1 rhinovirus, recurrent G1-G2 viral respiratory infections, G3 eosinophilia). All 3 pts were in a CMR at the time of treatment discontinuation.</p><p><b>Conclusion:</b> R+epco achieves high CMR rates in patients with high tumor burden FL, and debulking therapy with R may lower the risk of grade 2+ CRS. Based on these encouraging resul","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_227","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A GLOBAL PHASE 1B STUDY OF JNJ-90014496, A CD19/CD20 BI-SPECIFIC CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY, IN RELAPSED/REFRACTORY (R/R) LARGE B-CELL LYMPHOMA (LBCL)","authors":"K. Patel, J. M. Rhodes, L. Mountjoy, J. H. Christensen, M. Hutchings, P. Shaughnessy, N. Farhadfar, C. Tam, J. H. Baird, A. Ramakrishnan, M. Jak, K. Dorritie, A. Barraclough, D. Morillo, Y. Serroukh, M. Schwede, A. Abdulgawad, L. Magnano, M. O'Reilly, J. Kuruvilla, Y. Koh, U. Farooq, W. S. Kim, J. Bussolari, M. Beelen, J. S. Larsen, M. Suraneni, J. Wu, L. Slaets, A. Perales-Puchalt, A. Banerjee, M. Ku","doi":"10.1002/hon.70093_104","DOIUrl":"https://doi.org/10.1002/hon.70093_104","url":null,"abstract":"<p><b>Introduction</b>: CD19 CAR T-cell therapies have transformed the treatment (tx) of R/R LBCL, with complete response rates (CRR) of up to 58% in 3L or greater setting. However, most patients (pts) relapse, in part due to antigen escape. Dual targeting of 2 validated antigens may overcome drug resistance. In a first-in-human study in China, C-CAR039, an autologous anti-CD19/CD20 bispecific CAR T-cell therapy, showed a CRR of 86% in pts with R/R LBCL and PFS and OS were not reached at 30mo median follow up (FU). We report results from the first global phase 1b study of JNJ-90014496 (formerly C-CAR039) in adult pts with R/R LBCL (NCT05421663).</p><p><b>Methods</b>: Dose levels: 2.0 million (M) CAR+ T-cell/kg (weight-based); 150M and 75M CAR+ T-cells (fixed). Primary endpoints: safety and RP2D. Secondary endpoints: objective response rate (ORR), CRR, time to first response, pharmacokinetics (PK).</p><p><b>Results</b>: As of February 2025, 48 pts with CAR T-naive, heavily pretreated R/R LBCL were infused: 2.0M CAR+ T-cells/ kg, <i>n</i> = 18; 150M, <i>n</i> = 8; 75M, <i>n</i> = 22. 46% had ≥ 2 prior lines of therapy; 65% had bridging therapy. Median FU was 6mo.</p><p>Across all doses, 38 (79%) pts had CRS (grade [G]1, 52%; G2, 23%; G3, 4%): median time to onset and median duration of 3d (range, 1–6) and 5d (range, 1–42), respectively. 7 (15%) pts had ICANS (G1, 8%; G3, 6%): median onset and median duration of 3d (range, 3–12) and 8d (range 1–89), respectively. G3/4 and serious tx-emergent adverse events (TEAEs) were reported in 40 (83%) and 12 (25%) pts, respectively. No tx-related deaths occurred. G3/4 TEAEs ≥ 15% frequency were neutropenia (77%), leukopenia (21%), anemia (19%), and thrombocytopenia (17%); 6% of pts had G3 infections.</p><p>In 42 evaluable pts, investigator-assessed ORR and CRR by Lugano criteria were 90.5% (95% CI: 77.4–97.3) and 76.2% (95% CI: 60.5–87.9; Figure), respectively. Median time to response was 1.0mo (range, 0.8–1.9).</p><p>At RP2D of 75M CAR+ T-cells (<i>n</i> = 22), 19 (86%) pts had CRS (G1, 68%; G2, 18%; no G3/4). 1 (5%) pt had G1 ICANS (no G3/4 ICANS). At RP2D, 17 (77%) pts had G3/4 TEAEs and 5 (23%) pts had serious TEAEs. G3/4 TEAEs ≥ 15% frequency at RP2D were neutropenia (68%) and lymphopenia (18%); 1 pt had G3 infection.</p><p>At RP2D in 20 evaluable pts with 3-mo median FU, ORR was 95.0% (95% CI: 75.1–99.9) and CRR was 80.0% (95% CI: 56.3–94.3; Figure).</p><p>JNJ-90014496 C<sub>max</sub> and AUC<sub>0-29d</sub> at 75M CAR+ T-cells were comparable to 2.0M CAR+ T-cells/kg and 150M CAR+ T-cells. Median t<sub>max</sub> was seen on Day15 at 75M CAR+ T-cells versus on Day13 at other doses. High inter-pt variability was seen at each dose.</p><p><b>Conclusions:</b> The safety, efficacy, and PK profile support selection of 75M CAR+ T-cells as the RP2D of JNJ-90014496 in R/R LBCL. CRR of 80% and no G3/4 ICANS/CRS from this first global study are promising, confirm previous findings in Chinese pts, and compare favorabl","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_104","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BENDAMUSTINE SUPERCHARGE PLUS BRENTUXIMAB VEDOTIN AS EARLY SALVAGE FOLLOWING FAILURE OF 2 ABVD CYCLES IN HL: LONG-TERM RESULTS OF A RETROSPECTIVE MULTICENTER STUDY","authors":"C. Giordano, M. Picardi, N. Pugliese, A. Vincenzi, S. Avilia, L. De Fazio, M. Lamagna, R. Reina, A. Scarpa, A. Lombardi, E. Vigliar, G. Troncone, M. Mascolo, C. Mainolfi, R. Fonti, S. Del Vecchio, V. Damiano, R. Bianco, F. Trastulli, M. Annunziata, A. Salemme, M. Carchia, F. Pane","doi":"10.1002/hon.70094_360","DOIUrl":"https://doi.org/10.1002/hon.70094_360","url":null,"abstract":"<p>Treatment intensification with salvage therapy, and high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) is the best course of action for patients aged ≤ 60 years with classic Hodgkin lymphoma (c-HL) who fail to obtain complete metabolic remission (CMR) to first-line therapy. However, the clinical impact of early treatment intensification in patients showing positron emission tomography (PET)-positive evaluation after two cycles of ABVD remains to be confirmed. Theoretically, sequential brentuximab vedotin and bendamustine supercharge, that is, Bv+Bs<sub>21</sub>, as 3-day outpatient i.v. infusions of 1.8 mg/kg Bv on day 1 and Bs on days 2 and 3 at a fixed dose of 120 mg/m<sup>2</sup>/day, is a promising salvage regimen in this setting. We carried out a multicenter retrospective study (NCT06295211) including 50 adult patients with c-HL who had PET-positive (Deauville scale score ≥ 4) scans after two cycles of ABVD from 1 September 2013 to 1 September 2023. In all, 46 of the 50 collected patients were enrolled (median age, 37 years; range, 19–60). In fact, 42 cases received the four 3-week courses of Bv+Bs<sub>21</sub> followed by ASCT, four cases received the scheduled Bv+Bs<sub>21</sub> regimen without ASCT (patient’s decision), and four patients were excluded for alternative salvage regimens (<i>n</i> = 3) and insufficient information (<i>n</i> = 1). The primary endpoint was 5-year progression-free survival (PFS) calculated for patients receiving four courses of Bv+Bs<sub>21</sub> plus HDT and ASCT, and for those who received only four courses of Bv+Bs<sub>21</sub>. Secondary endpoints were the overall response rate, overall survival (OS), toxicity, peripheral blood stem cell (PBSC) collection and bridge to transplant, and feasibility of Bv+Bs21 regimen. With a median follow-up of 60 months (range, 7–132 months), the overall enrolled population PFS rate was 82% (86% for patients undergoing ASCT and 50% for those not receiving ASCT). The PFS stratified according to the pre-salvage treatment FDG-PET was 100% for DS score of 4 (<i>n</i> = 12) and 78% for DS score 5 (<i>n</i> = 34). With a median follow-up of 60 months, the 5-year OS rate of the entire analyzed population was 90%. After Bv+Bs<sub>21</sub> regimen, 42 patients obtained CMR and four partial metabolic remissions, with a rate of overall response of 100%. PBSC mobilization and harvest were successful in all cases, with a median CD34+ cells/kg yield of 4.1 × 10<sup>6</sup> (range, 1.9–5.1 × 10<sup>6</sup>). Overall, the most common adverse events were hematological of any grade, while, due to the specific premedication against acute toxicity during the i.v. administration of Bv+Bs<sub>21</sub>, serious infusion related reactions occurred only in three patients. All patients were efficacy-evaluable patients having completed four courses of Bv+Bs<sub>21</sub>: ≤ 10% of patients received < 85% of the planned treatment. In our study, early treatment intensificat","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_360","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MATCH-ADJUSTED COMPARISON OF EPCORITAMAB VERSUS NON-ANTHRACYCLINE CHEMOIMMUNOTHERAPY IN NEWLY DIAGNOSED DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS WITH HIGH CARDIOVASCULAR RISK","authors":"P. C. Johnson, E. Guo, G. Zhang, T. Wang, V. Patel, A. Mutebi, M. Atiya, J. Ukropec, A. Wang, S. Diness Vindeløv, J. Darrah","doi":"10.1002/hon.70094_291","DOIUrl":"https://doi.org/10.1002/hon.70094_291","url":null,"abstract":"<p><b>Introduction:</b> Anthracycline-containing (AC) chemoimmunotherapy (CIT) regimens may be unsuitable for patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who are older and/or have specific comorbidities, due to elevated risk of cardiovascular toxicities. Consequently, pts with high-risk cardiovascular (HRCV) status are often treated with non-AC CIT. In the EPCORE DLBCL-3 (NCT05660967) trial, epcoritamab (epcor) monotherapy (mono) showed promising efficacy and manageable safety in pts with newly diagnosed DLBCL and HRCV status (Morschhauser F et al. <i>Blood.</i> 2024;144:867). This analysis compares the efficacy of epcor mono versus non-AC CIT in pts with newly diagnosed DLBCL and HRCV status.</p><p><b>Methods:</b> Individual pt data for first-line (1L) epcor from the EPCORE DLBCL-3 trial were compared with pts treated with 1L non-AC CIT in the real-world setting. Pts diagnosed with DLBCL from 2007–2017 were identified from the US National Cancer Institute Surveillance, Epidemiology, and End Results database for initial diagnosis records and linked to the US Medicare database for treatment details using diagnosis codes (ICD-O-3: 9680/9688). Non-AC CITs included R-CVP (rituximab, cyclophosphamide, vincristine sulfate, and prednisone) or R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, and oral prednisolone) and BR (bendamustine and rituximab). HRCV status was defined using the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology criteria (Lyon AR et al. <i>Eur J Heart Fail</i> 2020;22:1945) and based on age and/or presence of comorbidities, including heart failure, valvular disease, myocardial infarction, coronary revascularization, hypertension, diabetes, or kidney disease. Inverse probability of treatment weighting was used to balance treatment cohorts on key available variables: age, gender, Ann Arbor stage, HRCV score, and postdiagnosis time-to-treatment. The primary endpoint was overall survival (OS). Hazard ratios (HRs) were estimated by weighted Cox regression models; time-to-event Kaplan-Meier curves were compared using log-rank tests.</p><p><b>Results:</b> Eighty-one pts receiving non-AC CIT and 45 receiving epcor were included. Before adjustment, the epcor cohort had fewer females (60.0% vs. 70.4%), fewer pts aged ≥ 80 years (82.2% vs. 95.1%), fewer pts with Ann Arbor stage III/IV (66.7% vs. 72.8%), and lower mean HRCV score (7.0 vs. 8.4). Adjusted OS was significantly improved in epcor (median OS not evaluable) versus non-AC CIT cohorts (median OS 10.2; HR 0.30 [95% CI: 0.14–0.66; <i>p</i> = 0.0027]). Subgroup analyses were consistent for non-AC CIT regimens: epcor versus R-CVP/R-CEOP (HR 0.34 [95% CI: 0.16–0.74]; <i>p</i> = 0.0067]) and epcor versus BR (HR 0.21 [95% CI: 0.08–0.56]; <i>p</i> = 0.0019) (Figures A–C).</p><p><b>Conclusions:</b> In the 1L treatment of DLBCL with HRCV status, epcor mono demonstrated significantly improved OS versus non-AC","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_291","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MULTI-OMICS DISSECTION OF EBV-DRIVEN HETEROGENEITY, METABOLIC REMODELING, AND TUMOR CELLULAR LANDSCAPE IN ENKTL PROGRESSION","authors":"J. Liang, K. Du, W. Xu","doi":"10.1002/hon.70094_195","DOIUrl":"https://doi.org/10.1002/hon.70094_195","url":null,"abstract":"<p><b>Introduction:</b> ENKTL is an aggressive lymphoma associated with EBV infection. While predominantly involving the upper aerodigestive tract (UAT) with better-prognosis early-stage disease (<b>Model-I</b>), advanced UAT-ENKTL (<b>Model-II)</b> and non-UAT (NUAT; <b>Model-III</b>) exhibit worse survival outcomes, validated in our 341-patient cohort. We utilized multi-omics approach integrating EBV virome analysis with <b>tumor microenvironment</b> and <b>metabolic reprogramming</b> to decipher the molecular drivers of clinical heterogeneity.</p><p><b>Methods:</b> The study enrolled 65 ENKTL patients (pts) from our center. We profiled using DNA-target gene sequencing (<i>N</i> = 42), RNAseq (<i>N</i> = 35), metabolomic assay (<i>N</i> = 42) and scRNAseq with EBV tag (<i>N</i> = 23) (Figure A).</p><p><b>Results:</b> We classified ENKTL into five groups: early-stage TN (<b>GroupA</b>), early-stage PD (<b>GroupB</b>), advanced UAT-ENKTL TN (<b>GroupC</b>), non-UAT TN (<b>GroupD</b>), and non-UAT PD (<b>GroupE</b>). Single-cell RNAseq (<i>n</i> = 280,939 cells) revealed T/NK cells, macrophages, and fibroblasts as predominant cell types (Figure B). By leveraging EBV tags at single-cell resolution, we characterized EBV infection patterns, showing predominant infection of NK cells (10%–67%, except NK_C13) and Teff cells (Figure C). Contrary to prior understanding, all EBV+ NK/T cells exhibited latency type I infection (Figure D). EBV+ NK cells were more prevalent in nasal versus non-nasal lesions and in PD versus TN lesions (GroupB > A, E > D). InferCNV analysis identified malignant NK cells, and they distributed in distinct groups with different functions (Figure E). Widely distributed NK_C1/C3 displayed functional trends aligned with the above. Bulk RNAseq validated the associations of NK_C4/C8 with advanced stages and poor prognosis by ssGSEA score (Figure F-G). EBV+ NK_C3/C8/C11/C12/C14 showed enhanced DNA modification and innate immunity, whereas EBV- NK cells mediated adaptive immunity, migration, and energy metabolism (Figure H). Gene module analysis uncovered two mutually exclusive modules: Module 4 featured immune activation (NK_C1/C2/C4), while Module 8 involved metabolic reprogramming (glycolysis/nucleotide metabolism) linked to poor prognosis (Figure I–L). Serum metabolomics revealed lipid metabolism enrichment in Model-III versus deficiency in Model-I. Monocle2 analysis demonstrated increasing blast NK cells during progression, with early-stage pts dominated by mature NK cells retaining cytotoxic functions (Figure M–O). CytoTRACE analysis confirmed higher stemness in EBV+ versus EBV- NK subpopulations, supporting EBV-driven proliferation (Figure P). Spatial heterogeneity was observed in fibroblasts: groupA/B/C contained Fibroblasts_MMP1 mediating ECM remodeling, while groupD/E featured Fibroblasts_ADH1B involved in antigen presentation and IFN signaling (Figure Q–S).</p><p><b>Conclusions:</b> In this largest multi-omics study focu","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_195","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"THE TOLL-LIKE RECEPTOR 7/8 PATHWAY HAS PROGNOSTIC SIGNIFICANCE AND IS A THERAPEUTIC TARGET IN CNS LYMPHOMAS","authors":"H. Geng, M. Randall, A. Ballapuram, L. Chen, C. Yung, M. Lu, C. Lowell, J. L. Rubenstein","doi":"10.1002/hon.70093_116","DOIUrl":"https://doi.org/10.1002/hon.70093_116","url":null,"abstract":"<p><b>Introduction:</b> The tumor microenvironment (TME) likely contributes to therapeutic resistance in CNS lymphomas (CNSL). Tumor-associated myeloid cells (TAMs), both macrophages and microglia, likely suppress the adaptive immune response and facilitate lymphoma progression via several mechanisms. Stimulation of TAMs via toll like receptors (TLRs) may potentiate an anti-tumor immune response.</p><p><b>Methods:</b> We evaluated the phenotypes and prognostic significance of TAMs in clinical investigations and preclinical models and are investigating the pharmcodynamic impact of systemic and intratumoral injection of a TLR 7/8 agonist in a syngeneic A20 model of CNSL.</p><p><b>Results:</b> Reductions in anti-tumor M1 TAMs in the TME, with transcriptional features of IFN-ϒ activation, are associated with tumor progression in patients with relapsed CNSL treated with rituximab, methotrexate and lenalidomide. IFN-ϒ knockout mice exhibit accelerated CNS lymphoma progression in tumor models and TAMs from IFN-ϒ wild-type mice exhibit a transcriptional phenotype consistent with TLR7/8 pathway activation. Higher TLR8 expression by TAMs correlated with longer PFS in a discovery set of PCNSL cases, and was associated with longer OS and high CD8 expression in a multicenter validation series. Expression of TLR8 by human macrophages, differentiated from PBMCs, is induced with IFN-ϒ, yielding M1 macrophages, but not by IL-4. These data demonstrate that TLR8 is a novel marker of M1 macrophages with prognostic significance, and suggest that pharmacologic agonists of the TLR7/8 pathway have potential to activate the anti-tumor potential of TAMs in CNS lymphomas. In collaboration with Gilead, we performed preclinical evaluations of a human TLR8 agonist, which activates mouse TLR7, via stereotactic injection of non-tumor bearing brains in BALB/c mice, demonstrating pharmacodynamic potency and safety. Intra-CNS injection of TLR7 agonist, but not vehicle, induced marked and diffuse perivascular accumulation of Iba1+ /iNOS+ M1 macrophages. We detected accumulation of CD8+ T cells adjacent to the injection site in brains exposed to the TLR7/8 agonist, but not vehicle. These results demonstrate that pharmacologic activation of the TLR7/8 pathway induces accumulation of Iba1+ M1 macrophages, and CD8+ T cells, and suggest that TLR7 activation promotes macrophage entry via the cerebral vasculature, without toxicity. In a syngeneic CNS lymphoma model, weekly systemic administration of TLR7 agonist delayed intracranial tumor progression. Targeted intra-CNS administrations of TLR7 agonist, without systemic administration, resulted in tumor regression and at least a trend toward longer OS.</p><p><b>Conclusions:</b> These data suggest that pharmacologic activation of the TLR7/8 pathway, via systemic and/or intra-CNS delivery, is feasible and programs the myeloid TME to an anti-tumor phenotype, with significant translational therapeutic potential in monotherapy and combinatorial","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_116","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDK7 ENABLES THE FUNCTIONAL CROSSTALK BETWEEN LYMPHOMA AND MICROENVIRONMENT (TME) CELLS IN PERIPHERAL T-CELL LYMPHOMA (PTCL)","authors":"K. Kouidri, D. Fiore, M. V. Revuelta, N. Di Siervi, S. Joshi, C. Kayembe, G. Inghirami, L. Cerchietti, N. Zamponi","doi":"10.1002/hon.70093_118","DOIUrl":"https://doi.org/10.1002/hon.70093_118","url":null,"abstract":"<p><b>Introduction:</b> PTCL cell survival and proliferation depend on crosstalk with TME cells. The acquisition of pro-tumoral phenotypes in TME cells requires transcriptional changes, creating a therapeutic vulnerability. This is critical for improving treatment of PTCL-NOS lacking actionable alterations.</p><p><b>Methods:</b> RNA-seq and multiparametric imaging of PTCL patient samples. Drug screening in stromal-lymphoma cocultures. In vivo efficacy, RNA-seq and proteomics of PTCL-NOS PDX.</p><p><b>Results:</b> To identify pro-tumoral TME pathways, we analyzed the cellular constitution and activity of PTCL TME using functional signature deconvolution (<i>n</i> = 845). Among four biologically and clinically relevant TME categories, we identified one with high pro-tumoral-polarized macrophages and cancer-associated fibroblasts (CAF). We established a co-culture of PDX-derived PTCL-NOS lymphoma cells (PDX-IL2) with matched CAF (PDX-IL2-CAF). PDX-IL2-CAF improved PDX-IL2 cell survival specifically, while mismatched PDX-CAF from four other PTCL PDX did not. RNA-seq of matched PDX-IL2-CAF showed upregulation of \"transcription\", \"DNA replication\", \"RNA POL2” and the \"CDK7 complex\". This suggests that CDK7, by enabling transcription initiation, is required to maintain the educated phenotype. We showed that CDK7 inhibition decreases oncogene-induced transcription, causing cytotoxicity in PTCL cells. To determine if CDK7 is required for establishing cell state-induced transcription in CAF, enabling crosstalk with lymphoma cells (LyC), we administered low-dose (10 mg/kg per day) of the covalently selective CDK7 inhibitor YKL5124 to PDX-IL2 bearing mice and conducted RNA-seq and proteomics of isolated LyC and CAF at two time points. Ligand-receptor analysis identified CXCL12 in CAF and CXCR4 in LyC as the main CDK7-dependent crosstalk interaction. In CAF, the acquisition of \"cytokine signaling\" and \"immune cell modulation\" phenotypes was CDK7 dependent. Functional validation using cytokine profiling of YKL5124-treated PDX-IL2-CAF showed decreased secretion of pro-inflammatory cytokines IL6, CCL2, ICAM1, and CXCL1. Meanwhile, LyCs showed activation of pathways likely to compensate for decreased CDK7-dependent transcription including \"stress response,\" \"RNA processing\" and \"protein synthesis\" with upregulation of ALYREF and EIF4E, previously identified as XPO1 targets. Because this may represent new therapeutic vulnerabilities, we conducted a viability screening of PDX-IL2 CAF and LyC co-cultures with a library of 40 clinical-phase compounds targeting these compensatory mechanisms. Two drugs, targeting XPO1 (Selinexor) and translation (Omacetaxine), were the most potent combination with YKL5124. These are being tested in PTCL-NOS PDX mice.</p><p><b>Conclusion:</b> CDK7 activity in both lymphoma and CAF is required to establish functional pro-tumoral crosstalk that can be exploited therapeutically.</p><p><b>Research</b> <b>funding declaration:</b> Funding for","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_118","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}