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Abstract Introduction: CTCLs are rare, heterogeneous non-Hodgkin lymphomas (NHL) with significant regional variability in treatment patterns. Prospective studies characterizing CTCL management, particularly in racially and ethnically diverse populations, remains limited. The LEO-MER multi-center prospective cohort study (NCT02736357) is designed to address the persistent disparities in outcomes research by enrolling historically underrepresented groups of patients diagnosed with lymphoma across the United States (US). Here, we present a real-world analysis of CTCL patients that reflects US academic practice, evaluating treatment patterns, as well as prognostic factors influencing survival outcomes. Methods: Patients aged ≥18 years with newly diagnosed CTCL were prospectively enrolled in either the University of Iowa/Mayo Clinic MER cohort (2002-2015) or the expanded LEO cohort (2015-2020), which included 8 US academic centers. Standardized protocols were used to abstract clinical, pathologic, treatment, and outcome data from medical records. ANOVA/Kruskal-Wallis and Fisher's/chi-square tests were used to compare patient distribution across demographic and clinical characteristics based on data distribution and sample size. Overall survival (OS) was calculated from diagnosis to death or last follow-up. Survival analyses employed Kaplan-Meier estimation supplemented by Cox proportional hazards modeling. Results: The LEO-MER cohort enrolled 223 CTCL patients (91 MER and 132 LEO). Subtypes included mycosis fungoides (MF, n=155, 69.5%), Sézary syndrome (SS, n=22, 9.9%), primary cutaneous anaplastic large-cell lymphoma (n=17, 7.6%), subcutaneous panniculitis-like T-cell lymphoma (n=11, 4.9%), cutaneous CD4+ small/medium T-cell lymphoproliferative-disorder (n=9, 4%), and other rarer CTCL subtypes (n=9, 4%). Among the MF/SS cohort, median age was 64 years (Range: 18-89 years), 58.2% (n=103) were male and race/ethnicity distribution included White (n=123, 69.5%), Black (n=29; 16.4%) and others/unknown (n=25; 14.1%). Stage distribution included 62.7% with early-stage (ES) MF (IA-IIA, n=111), 37.2% with advanced-stage (AS) MF (IIB-IVB, n=66). To complete diagnostic workup, T-cell receptor (TCR) testing was performed in 52.6% of skin biopsies (n=92) and 62.5% of blood samples (n=110), with clonal detection rates of 75% (69/92) in skin and 51.8% (57/110) in blood. Paired TCR matching between skin and blood samples was performed in 31.6% (n=56) of cases, demonstrating 53.6% (30/56) concordance. Blood flow cytometry data were reported in 80.1% (89/111) and 84.4% (56/66) of ES and AS MF cases, with T-cell population being detected in 7.2% (8/111) and 62.1% (41/66) of ES and AS cases. Nodal biopsies were obtained in 23.4% (n=41) of patients and clonality assessment was reported in 18.6% (33/177) of these cases. The MF/SS cohort's lifetime treatment exposure data (n=160) revealed topical skin-directed therapies alone (n=49, 31.8%) as the most common approach followed by lifetime exposure to topical skin-directed and systemic therapies (n=45, 29.2%) followed by multimodal exposure of topical skin-directed, radiation and systemic treatments (n=30, 19.5%). Only 5.6% of patients were enrolled in a clinical trial. First-line (1L) systemic regimens were predominantly a) immunomodulatory agents (n=47, 29.3%); including oral retinoid (n=20), extracorporeal photopheresis (n=18), interferon (n=9) followed by b) chemotherapy (n=30, 18.7%) and c) targeted therapies (n=17, 10.6%) including Brentuximab Vedotin (n=6), Romidepsin (n=5), Mogamulizumab (n=3), Vorinostat (n=2) and Pralatrexate (n=1). Multivariable analysis predicting 1L systemic treatment initiation demonstrated a significant association with presence of N2/N3 stage (N2/N3 vs N0/N1: Odds Ratio (OR): 5.45) and elevated LDH (OR: 5.30). At median follow-up of 91.1 months (mon), median OS was 122.3 mon (95% confidence interval 67.2-159.2 mon). In subset analyses, Black race (p=0.001) and SS (p=0.0001) were associated with worse OS outcomes. Conclusion: We present initial data from our prospective LEO-MER cohort, a large US-based multicenter consortia. Our findings demonstrate variability in both diagnostic staging and treatment approaches for MF/SS patients. The cohort demonstrated worse outcomes with high-risk disease and Black race/ethnicity. These findings warrant further study on the impact of underlying social determinant factors, given the variability noted in this population.

Abstract Introduction With a median age of 60-70 years at diagnosis, many patients with MCL are ineligible for aggressive treatment. Bendamustine and rituximab (BR) is a standard therapy for older patients with MCL. Venetoclax (VEN) has shown pre-clinical evidence of synergy with chemotherapy. Thus, PrE0405 was designed to evaluate the addition of VEN to BR in previously untreated older patients with MCL. We have previously reported on response rate and short-term survival (Portell et al. ASH 2023). Here, we update survival and include minimal residual disease (MRD) at end of treatment (EOT). Methods Eligible patients included those that were previously untreated and diagnosed with MCL by presence of t(11;14) or cyclin D1 expression. Patients must have been ≥60 years of age at the start of therapy with a good performance status (ECOG 0-2). Adequate marrow and organ function was required, specifically a creatinine clearance ≥ 40 ml/min. Eligible subjects were treated with bendamustine 90mg/m2 D1-2 and rituximab 375mg/m2 IV D1 every 28 days for a planned 6 cycles of therapy. For patients ≥75 years, 70mg/m2 of bendamustine was allowed. VEN was given concurrently with BR. During Cycle 1, VEN was dose escalated weekly, as done in chronic lymphocytic leukemia, from 20mg to 200mg. For Cycle 2-6, VEN was administered as 400mg PO daily on days 1-10 only. Maintenance rituximab was encouraged but was per investigator discretion. Primary end point was PET-negative complete remission (CR) at EOT by Lugano Criteria and was confirmed by a negative bone marrow biopsy if involved at screening. MRD was assessed at EOT by next-generation sequencing (Clonoseq). Amended accrual goal was 33 patients with a planned 32 being eligible and treated. This provided an 81% statistical power to detect a 17% difference in CR rate (from 60% [E1411, Smith et al Blood 2024] to 77%) using an exact binomial test with a 1-sided alpha of 11.6%. Thus, BR-VEN would be considered promising if 23 or more subjects attained a CR. Results From 1/2020 to 3/2022, 33 subjects were enrolled, deemed eligible, and treated on study. Subjects were followed until 7/2024. Median age was 71 (range 61-80) and 76% (n=25) were male. All but 1 subject (97%, n=32) were White. MIPI was high in 67% (n=22), intermediate in 27% (n=9) and low in 6% (n=2). Ki67 was available in 25 (76%) subjects and was ≥30% in 14 (56%) and ≥50% in 7 (28%). Only one subject started bendamustine treatment at 70mg/m2; though 6 others had dose reductions during treatment. Thirty (90%) subjects completed all 6 cycles of therapy. Maintenance rituximab was administered in 19 (56%) of subjects and 9 completed all 12 recommended doses. Treatment was generally well tolerated. During BR-VEN, Grade ≥3 treatment-related adverse events (TRAE) occurring in >10% (i.e., 4 or more) of subjects were neutropenia (n=8, 24%), and thrombocytopenia (n=5, 15%). Other common TRAE of all grades were nausea/vomiting (n=19, 58%), diarrhea (n=10, 30%), and fatigue (n=19, 58%). At EOT with BR-VEN, overall response and CR rate was 97% (32 of 33) and 85% (28 of 33) respectively. The study met its primary endpoint of at least 23 subjects with a CR best response (p=0.002). EOT MRD sample (blood or marrow aspirate) was available for 28 subjects (85%). At EOT, MRD was undetectable for 100% (n=28) of evaluable subjects at a sensitivity of 10-4 and 10-5. At a sensitivity of 10-6, 64% (n=18) were undetectable, 4% (n=1) were detectable and 32% (n=9) were indeterminate. With a median follow up of 39.1 months, 3-year progression free survival (PFS) was 68.9 and 3-year overall survival (OS) was 70.0%. There were 11 total PFS events during follow up. Four subjects in remission died due to COVID-19, 1 died from influenza, one died from HSV encephalitis, and 2 others died from other causes. Two subjects died shortly after progression and 1 subject is alive following disease progression. As this study enrolled during the height of the COVID-19 pandemic, a sensitivity analysis was performed censoring the COVID-19 attributable deaths – PFS and OS at 3 years was 78.7% and 80.0%. Conclusions BR-VEN was generally well tolerated as induction therapy in older patients with MCL. It achieved a high CR rate of 85% with 100% MRD undetectable rate at 10-5 sensitivity in those evaluable. However, there were competing risks for survival in this older population as, of the 11 PFS events, only 3 events were due to progression; 8 were due to death without progression.

Abstract Introduction: CAR-T therapy has transformed cancer therapy. with its first Food and Drug Administration (FDA) approved product in August 2017. Given the expanding indications and growing experience, particularly with management of immediate toxicities requiring specialized expertise such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity syndrome (ICANS), FDA recently removed the Risk Evaluation and Mitigation Strategies (REMS) for CD19 and BCMA targeting CAR-T on June 26th2025. In particular, given that CRS and ICANS typically occur in the first 2 weeks post CAR-T infusion, the minimum required stay near CAR-T treatment center is reduced from one month to 2 weeks. While this could reduce treatment burden for patients (pts) who need to travel away from home to receive CAR-T, there is a need to update the transition of care from CAR-T center to pts' local oncology practice. Pts carry in their rate of recovery and have varying supportive care needs in the second half of the month post CAR-T infusion. To assist with care transition and planning, we examine the use of AI multimodal large language model (LLM) to predict patients' supportive care needs 2 weeks after CAR-T infusion based on the clinical data at the time of CAR-T evaluation, prior to leukapheresis. This timepoint was selected to also maximize travel, lodging and caregiver planning for pts and family as well. Methodology: Pts who were treated with FDA-approved CAR-T at Mayo Clinic Rochester between December 2022 and June 2025 were examined. Based on experiences with referral practices in the Midwest region, we defined patients with high monitoring needs as those who between day 14-30 post CAR-T had either hospital admission due to recurrent CRS or ICANS or required transfusion of more than 1 blood product per week (red blood cell or platelets). Others were classified as low monitoring needs. Clinical notes, labs, vital signs and electrocardiogram at the time of CAR-T evaluation were abstracted and summarized by Gemini LLM for association with patients with high versus low monitoring needs post CAR-T. Model was developed and tested for predicted needs and concordance with actual outcome of these pts. Results: Among the 362 pts who received FDA approved CAR-T in the timeframe, 84 pts had high monitoring needs. An additional 84 pts with low monitoring needs were randomly selected from 278 pts. These were divided into a training cohort and test cohort of 84 pts each, with 42 pts with high and 42 pts with low monitoring needs. Demographics of the two cohorts displayed no statistical difference. LLM analysis of the clinical data at the time of CAR-T eval identified 5 categories associated with risk for high monitoring needs: 1) Disease status (clinical notes about bulky, progressive disease or CNS involvement); 2) inflammatory and tumor burden markers (CRP, LDH); 3) hematologic status (platelet, plt; neutrophil count ANC); 4) renal function; 5) performance status. Using common clinical lab parameter convention (platelets <100, ANC< 1, CrCl< 30ml/min), and prioritizing for not missing pts with high monitoring needs, LLM model was defined to predict patients for high monitoring needs if high risk feature was identified in category 1 or any category combinations; whereas patients with no high risk feature or only 1 category that is not disease status was predicted as low monitoring needs. In this model, the sensitivity was 85.7%, specificity 23.8%, F1 score 65.5%. Applying this model to test cohort 2, the sensitivity was 83.3%, specificity 28.6%, and F1 score 65.4%. Discussion: We demonstrate proof-of-concept that LLM can be used to analyze clinical data at the time of evaluation for CAR-T eligibility to predict for supportive care needs post treatment. Not surprisingly, features identified by LLM to be associated with high monitoring needs are those previously reported by us and others at the time of CAR-T evaluation and or pre-lymphodepletion to be associated with risk for cytopenia, infection, hospitalization and non-relapse mortality. Based on the summary output generated by LLM, additional opportunities for classification methods were identified to improve specificity and balanced accuracy of the LLM model. This is a promising tool for further development to assist clinicians and patients to plan their treatment journey.

Abstract Background Nodal peripheral T-cell lymphomas (nPTCLs) are a challenging group of non-Hodgkin lymphomas that frequently recur after or are refractory to first line (1L) treatment. Chemotherapy options in the relapsed or refractory (R/R) setting are limited. The incorporation of non-cytotoxic agents including antibody drug conjugates, immune checkpoint inhibitors, epigenetic modifiers, and phosphatidylinositol 3-kinase inhibitors offers new therapeutic potential and possibly better outcomes. We report on outcomes for patients (pts) with R/R nPTCL enrolled in the multi-center LEO-MER prospective cohort study (NCT02736357) who received second line (2L) therapy. Methods Six hundred and three adult pts with newly diagnosed nPTCL were prospectively enrolled in the University of Iowa/Mayo Clinic MER observational cohort (2002-2015) or the expanded LEO cohort (2015-2020). Secondary overall survival (sOS) was calculated from date of 2L treatment initiation to date of death or last follow-up. Secondary event-free survival (sEFS) was calculated from date of 2Ltreatment initiation to disease progression, initiation of 3rd line therapy, or death from any cause. sEFS and sOS were evaluated using Cox model and Kaplan-Meier estimator. Log-rank test was used to test the significance of difference between groups. Pts with concomitant B-cell lymphomas were excluded from this analysis. Results Thus far, 169 pts with nPTCL initiating 2L therapy were evaluated. Of these, 75 (44.4%) had PTCL-NOS, 63 (37.3%) had angioimmunoblastic T-cell lymphoma (AITL, inclusive of nodal T-follicular helper cell lymphoma), 20 (11.8%) had ALK-negative anaplastic large cell lymphoma (ALCL), and 11 (6.5%) had ALK-positive ALCL. At 2L treatment initiation, the median age was 64 with 86.1% of pts having advanced stage disease. Of the 108 pts with available international prognostic index (IPI) scoring, 46.3% had an IPI of ≥3. Thirty-four (20.1%) pts had received a consolidative autologous stem cell transplant (ASCT) in the 1L. A total of 86 pts (50.1%) had primary refractory disease (partial response, stable or progressive disease as best response to 1L therapy), 45 (26.6%) experienced early relapsing disease within 6 months of 1L therapy, and 38 (22.5%) had relapsed disease >6 months from 1L therapy. After a median follow-up of 7.1 years (yrs), median sOS was 1.52 yrs, and sEFS was 3.2 months (mos). There was no difference in sOS or sEFS regardless of timing of relapse. In keeping with other studies, ALK-positive ALCL pts had the best 5-year OS (70.1%) compared to other subgroups (ALK-negative ALCL 45.0%, AITL 30.4%; PTCL-NOS 21.3%). Lymphoma was the leading cause of death following 2L therapy, with a 2-year cumulative incidence of 49.2%. Eighty pts (47.3%) received only cytotoxic chemotherapy as second line (2L) therapy; ICE (41 (51.3%)) and gemcitabine-containing regimens were most common (14 (17.5%)). Seventy-five pts (44.4%) were treated with non-cytotoxic agents given as monotherapy or in combination with chemotherapy. The most common non-cytotoxic therapies were brentuximab vedotin (33 (44.0%)), romidepsin (17 (22.7%)) and immune checkpoint inhibitors (9 (12.0%)). Fourteen pts (8.3%) underwent palliative interventions involving radiation, steroids, or cyclosporine alone. Intent to proceed to transplant in the 2L was known in 158 pts (101 (63.9%) not intended, 57 (36.1% intended)). Following 2L treatment, 18 (10.7%) pts proceeded to consolidative ASCT and 10 (5.9%) to allogeneic transplant. Only 21 (12.9%) were treated on a clinical trial. Pts who received a non-cytotoxic agent had superior outcomes compared to pts receiving only chemotherapy; the median sOS was 30.4 mos (95% confidence interval [CI] 15.3, 53.52 mos) vs 11.7 mos ((95% CI 7.95,19.58); p=0.04; HR 0.67) and the median sEFS was 4.83 mos (95% CI 3.38, 10.09) vs 2.33 mos ((95% CI 1.71,3.02); p=0.02; HR=0.65). Conclusions We report here one of the largest prospective cohorts in R/R nPTCL. The LEO-MER cohort, despite its association with academic centers, shows poor outcomes regardless of refractory or relapsed disease, frequent inability to proceed to intended consolidative transplant, and low clinical trial participation in 2L, which corroborates findings from other registries (Jain 2025, Stuver 2019). Outcomes improved for pts treated with non-cytotoxic agents. Updated data including additional pts and subgroup analyses will be reported at the meeting.

Abstract Introduction: Reporting patient outcomes by CAR-T treatment centers is part of the accreditation requirement under the FACT (Foundation for Accreditation of Cell Therapy) Immune Effector Cell (IEC) Program standard. Currently, this is a time-consuming and manual process, making it increasingly difficult to sustain with the growing CAR-T applications and patient volume. The objective of this study is to evaluate how a Large Language Model (LLM) can be used to automate the abstraction and summarization of medical record for CAR-T toxicities. Methods: Clinical data from patients treated with CAR-T between January 2018 and June 2025, including hematology clinical notes, lab results, flowsheets, vital signs, and medication administration record, were used as the source of patient information. The American Society of Transplant and Cell Therapy (ASTCT) CAR-T toxicity grading guideline for cytokine release syndrome (CRS) and immune effector cell associated neurologic syndrome (ICANS) were used to define these toxicities. With the large context window of the LLM (Gemini 2.5 pro), we created a prompt by embedding both the patient data and the ASTCT guidelines for CRS and ICANS, along with an outline of specific information we aimed to abstract from the data. Additionally, the LLM was instructed to provide contextual justification for the data it extracted from patient information. The LLM-generated output included event onset date, resolution date, maximum grade, date of maximum grade, and medications given for management. The CRS and ICANS outcome reports generated by the LLM were then compared to the IEC compliance program data. Any discrepancies identified were reviewed manually. Results: Among patients (pt) treated with CAR-T in the specified timeframe, 47 were selected as training cohort. This cohort included pt with toxicities events, no events, and a mix of events of varying grades. For the test cohort, 66 pts who received CAR-T from March to June 2025 were included. Demographics for the training and test cohorts are reflective of evolving clinical practice (training, test cohorts: median age 69, 65; male 55%, 74%; lymphoma/leukemia 66%, 48%; multiple myeloma 34%, 52%; CD19 CAR-T 46%, 50%). Compared to data from the IEC compliance program, the LLM-generated summaries for CRS events demonstrated an accuracy of 90%, precision 95%, sensitivity 100%, specificity 80%, F1 score 97%, and Matthew's correlation coefficient 87%. For ICANS event, the LLM achieved an accuracy of 91%, precision 92%, sensitivity 92%, specificity 90%, F1 score 92%, Matthew's correlation coefficient 83%. Maximum grade, for both CRS and ICANS, were identified with >90% accuracy. However, dates for CRS and ICANS were less accurate, with the lowest accuracy noted in identifying the event resolution date, 45% for CRS and 67% for ICANS. Medical records were reviewed for all discrepancies between the LLM and the IEC Compliance Program data. The most common discrepancy was a mismatch in event resolution date, determined to be due to differing criteria used by the compliance team and the LLM prompt. Of note, a few discrepancies were attributed to missed information by the IEC Compliance Team, which was correctly identified and categorised by the LLM. An updated LLM prompt (LLMv2) was developed and applied to the test cohort. In version 2, the prompt was revised to include clearer instructions on how to summarize CRS and ICANS events, as well as new instructions on additional data elements to be summarized. The performance of LLMv2 on this cohort for CRS event identification was 100% across all categories (accuracy, precision, sensitivity, specificity, F1 score, and Matthew's correlation coefficient). For ICANS the LLMv2 achieved accuracy of 96%, precision 69%, sensitivity 100%, specificity 93%, F1 score 82%, Matthew's correlation coefficient 80%. Accuracy in identifying event resolution date improved significantly from 64% to 99%. Conclusions: Our study demonstrates that LLMs can significantly reduce the time required to abstract and summarize CAR-T toxicities, while maintaining high accuracy. One limitation of our study is that it is based on data from a single institution. However, plans are already underway to evaluate the use of LLMs in a multi-institutional setting.

Abstract Introduction: The real-world outcomes in patients (pts) with PCALCL in the era of targeted therapies like Brentuximab Vedotin (BV) is not well defined due to lack of large multicenter studies. We conducted a multicenter retrospective analysis (RWA) to assess patient and disease characteristics, treatment patterns, survival outcomes and impact of novel therapies in this rare type of cutaneous T cell lymphoma (CTCL). Methods: The analysis included 167 adult (≥18 years) patients (pts) with PCALCL across 9 academic institutions in the United States diagnosed between 01/2012 to 06/2022. The study was approved by the Institutional Review Boards at the respective sites. Demographic and disease factors were summarized using descriptive statistics. Overall survival (OS) and relapse-free survival (RFS) were estimated using Kaplan-Meier method and compared via log rank tests. Prognostic models included factors such as age, sex, race, performance status (PS), disease stage, type of initial lesion, presence of B symptoms, previous history of lymphomatoid papulosis and prior transplant. Prognostic factors for survival were assessed using both univariable and multivariable Cox proportional hazard models. Results: The median age at diagnosis was 61 (range 18-93) years. The majority of pts were male (55%) and white (82%), with good PS as indicated by an ECOG 0-1 (71%). The initial skin presentation consisted of tumors in 62% of the pts, while 34% presented with plaques or patches. Notably, no pts presented with erythroderma. Most pts underwent PET scan for staging at initial diagnosis (83%) with the majority having early-stage (IA-IIA) disease (86%). Furthermore, palpable lymph nodes (11%) and the presence of B symptoms (4%) were rare at diagnosis, and no pts had blood involvement. The most common sites of involvement were extremities (33%) followed by the head and neck (H&N) and trunk (31% each). Immunophenotyping revealed CD4 positivity in 59% of pts and CD8 positivity in 25%. The T cell receptor (TCR) rearrangement was positive in 28% of pts, though it was not completed in the majority of cases (72%). Most common initial treatments included localized radiation (61%) and surgical excision (19%). A small subset of pts received frontline systemic chemotherapy regimens such as cytotoxic chemotherapy (11%), BV (8%) and oral methotrexate (MTX) (8%). Approximately 7% of the pts had a stem cell transplant. Overall response rate (ORR) for radiation, oral MTX, BV and cytotoxic chemotherapy were 78% (CR:78% 74/100), 42% (CR:63% 6/12) and 39% (CR:67% 6/12), 89% (CR: 88% 15/18) respectively. At a median follow-up of 3.8 years (range 0.04-10.23), the median RFS and OS were 2.7 years (95% CI:1.86, 3.43) and 12 years (95% CI:10.6- NA) respectively. The estimated 3- and 5-year RFS are 46% (95% CI:0.38, 0.55) and 37% (95% CI:0.28, 0.46) respectively. The estimated 3- and 5-year OS were 89% (95% CI:0.82, 0.93) and 82% (95% CI:0.73, 0.88) respectively. At the time of the last follow-up, 79% were alive, while 21% were deceased. The cause of death (COD) was unknown in 50% of the cases and only 10% (3/of deaths were attributed to lymphoma. Other known CODs included infection (20%) and second malignancies 7%. On univariate analysis (UVA), age (p=.007), female sex (p=.04), ECOG PS 1-2 compared to 0 (p=.007) and prior transplant (p=.009) predicted for worse RFS. On multivariate analysis (MVA), only ECOG PS 1-2 (HR 2.31, 95 CI:1.06, 1.18, p=.009) and prior transplant (HR 5.38, 95 CI:2.30, 12.57, p=.0001) had a significant impact on RFS. Age and presence of B symptoms were strong predictors of OS on both UVA (age p=<.0001; B symptoms p=<.0001) and MVA (age: HR 1.12, 95 CI:1.06, 1.18, p=<.0001; B symptoms: HR 16.48, 95 CI: 3.69, 73.60, p=.0002). However, the impact of B symptoms should be interpreted with caution as only 4% of pts presented with this at baseline. On UVA, each one-year increase in age was associated with an 8.5% rise in the risk of death. ECOG PS 1-2 was associated with worse OS on univariate analysis (HR 2.62, 95% CI 0.99, 6.93, p=.05), but was not significant on MVA (HR 1.05, 95% CI 0.368, 2.974, p=.93). Conclusions: In this large RWA of PCALCL, excellent long-term survival was observed with predominantly skin directed frontline therapies. The use of systemic treatments, including BV, was infrequent as first line therapy. Older age and poor PS were significant predictors for reduced survival.

Abstract Background Previous studies in aggressive B-cell lymphoma demonstrate that patients with shorter diagnosis-to-treatment intervals (DTI) represent those with higher risk disease. This suggests that patients enrolled in clinical trials may carry a selection bias as they often have longer DTI than patients in the general population. This has important implications for clinical research design and the generalizability of clinical trials in aggressive lymphomas. However, the prognostic implications of DTI have not been evaluated in peripheral T-cell lymphomas (PTCL). Therefore, we examined DTI and its association with clinical factors and outcomes in a prospective observational cohort of patients with PTCL from the United States within the LEO (Lymphoma Epidemiology and Outcomes) and MER (University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource). Patients and Methods We evaluated patients enrolled to the MER (2002-2015) and LEO (2015-2020) cohorts with the following forms of PTCL: PTCL-not otherwise specified (PTCL-NOS, n=217), nodal T-follicular helper (TFH) cell lymphoma (nTFHL, n=153), anaplastic large cell lymphoma (ALCL), ALK positive (ALCL, ALK+, n=74), ALCL, ALK negative (ALCL, ALK-, n=95), enteropathy associated T-cell lymphoma (n=18), and monomorphic epitheliotropic intestinal T-cell lymphoma (n=2). Associations of DTI with clinical factors and outcomes were examined using Kaplan Meier and Cox models. Event free survival (EFS) was defined as the time from start of treatment to relapse/progression, start of 2nd line therapy, or death from any cause. Overall survival (OS) was defined as the time from start of treatment until death from any cause. DTI was defined as the number of days between the first diagnostic biopsy and the start of therapy. Patients who were initially observed or had DTI > 100 days were excluded. Results In 559 patients (229 MER and 330 LEO), median age was 60, 34% had IPI>2 and 71% were stage III/IV. 472 (84%) patients initially received anthracycline-based chemotherapy. Median DTI was 23 days (interquartile range (IQR): 12-39) and was similar in MER (21 days, IQR: 11-33) and LEO (25 days, IQR: 14-42). 168 (30%) patients had DTI 0-14 days, 178 (32%) 15-28 days, and 213 (38%) 29-100 days. Overall in the cohort, shorter DTI was associated with a worse 5-year OS (DTI 0-14 days: 43%; DTI 15-28 days: 53%; DTI 29-100 days: 58%, p<0.001) and 5-year EFS (DTI 0-14 days: 31%; DTI 15-28 days: 39%; DTI 29-100 days: 45%, p<0.001). In multivariable analyses, the association of DTI with outcomes remained consistent after adjusting for age and International Prognostic Index (IPI). Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B-symptoms, and higher IPI in both cohorts (all P < .003). DTI was not associated with age, sex, or distance from the LEO/MER center (all p>0.3). 6% patients with DTI of 0-14 days received 1L treatment on a clinical trial, compared to 11% with DTI 15-28 days and 13% with DTI 29-100 days, underscoring that patients with lower DTI may be underrepresented in clinical trials. When examining within PTCL subtypes, the association between short DTI (0-14 days) and inferior outcomes was most prominent in PTCL, NOS (OS HR=2.13, 95% CI: 1.52-2.94; EFS HR =1.49, 95% CI: 1.19-1.85). Associations between short DTI and outcomes were weaker in other subtypes: nTFHL (OS HR=1.28, 95% CI: 0.83-2.00; EFS HR =1.22, 95% CI: 0.82-1.81), ALCL, ALK-, (OS HR=1.30, 95% CI: 0.59-2.86; EFS HR =1.32, 95% CI: 0.68-2.56), ALCL, ALK+, (OS HR=1.05, 95% CI: 0.26-4.17; EFS HR =2.12, 95% CI: 0.84-5.26). Conclusion Shorter DTI is associated adverse prognostic clinical factors (LDH, stage, high IPI) and inferior EFS and OS in newly diagnosed PTCL. Patients with DTI ≤ 14 days, which represents approximately 1/3 patients with PTCL, may be underrepresented in clinical trials. Understanding of this selection bias should inform clinical trial design and interpretation. Future studies should consider strategies to minimize barriers to enrollment for patients with low DTI.

Abstract Introduction Histiocytic neoplasms (HN) are a rare, heterogeneous group of hematologic disorders derived from myeloid-dendritic cell lineages. The most common forms include Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD). These disorders are driven by recurrent activating mutations in the MAPK pathway, most frequently involving BRAF, MAP2K1, PIK3CA, KRAS, and NRAS. This discovery enabled a major therapeutic advance with the use of BRAF and MEK inhibitors, resulting in durable responses. For patients harboring KRAS mutations, MEK inhibitors (MEKi) remain the primary therapeutic approach. However, the impact of KRAS mutation subtypes on treatment response remains poorly understood. Our study aimed to characterize the spectrum of KRAS mutations in LCH, ECD, and RDD and evaluate the responses to MEKi, providing insights to guide future treatment strategies. Methods We conducted a retrospective review of patients with LCH, ECD, and RDD who were evaluated at Mayo Clinic or University of Alabama at Birmingham. Patients were included if next-generation sequencing identified a KRAS mutation. The response assessment was based on radiographic evaluation under the most recent Histiocyte Society consensus guideline. Results We identified 23 patients with a KRAS mutation: 17 females (73.9%) and 6 males (26.1%), with a median age at diagnosis of 61 years (range, 20–78). RDD accounted for 73.9% (17/23) and ECD for 26.1% (6/23); no KRAS mutations were detected in LCH patients. The most frequent KRAS variants were p.K117N (34.8%), p.G12D (17.4%), p.A146T (13.0%), p.G13C (8.7%), and p.G13D (8.7%), with additional variants including p.T58I, p.A59G, p.A146P, and p.A146V. Mutation distribution differed by disease group: p.G12D was more common in ECD (50%) than RDD (5.9%) (p=0.01), whereas p.K117N occurred in 47.1% of RDD and was absent in ECD. Regarding treatment, 57% (13/23) received MEKi, all initially cobimetinib, with 1 patient switched to trametinib due to progression. Of the 10 patients who did not receive MEKi, 1 was treated with vemurafenib for a concurrent BRAF p.V600E mutation; 3 remained on observation; 2 underwent surgery without recurrence; 3 received other systemic therapies including corticosteroid, methotrexate, rituximab, lenalidomide, or sirolimus; and 1 developed diffuse large B-cell lymphoma, treated with R-CHOP. The overall response rate in the 12 patients on MEKi (excluding 1 patient too early for assessment) was 75%—3 (25%) CR and 6 (50%) PR (including 1 who initially progressed on cobimetinib but responded to trametinib). All 3 non-responders had RDD. Among the 5 patients with p.K117N, 3 had no response to cobimetinib, 1 achieved PR, and 1 achieved CR; notably, 1 non-responder switched to trametinib and achieved PR in 2 months. All 3 patients with codon 146 mutations achieved PR. Of the 2 patients with p.G12D, 1 achieved CR with a co-occurring MAP2K1 mutation, and 1 had no response. No additional genotype–response patterns were observed. Similar heterogeneity has been reported in prior studies. In a phase II cobimetinib trial, an ECD patient with p.R149G achieved PR, whereas another ECD patient with p.G12R and an LCH patient with p.G13C achieved CR in the presence of co-occurring ARAF and NRAS mutations, respectively. A retrospective cohort described an ECD patient with p.K117N achieving PR on dabrafenib and trametinib with a concurrent BRAF mutation and another with p.G12A achieving PR on trametinib. In a multicenter analysis of trametinib, a patient with p.A59T (co-occurring BRAF and NRAS mutations) had no response, whereas another with p.A146P achieved PR. Collectively, these findings, together with our data, underscore that KRAS-mutated histiocytoses exhibit heterogeneous responses to MEKi, likely influenced by variant type and co-mutations. Discussion KRAS mutations represent an important subset of MAPK pathway alterations in HN, although their prevalence varies by disease type and appears extremely rare in LCH, with no cases identified in our cohort. The most common variants include p.K117N and p.G12D, which may be linked to suboptimal response to MEKi in the absence of concurrent MAPK pathway alterations. As MEKi acts downstream, efficacy likely depends on the level of pathway activation conferred by specific KRAS variants. Larger studies are needed to confirm these observations and identify mutation-specific predictors to guide personalized treatment.

Abstract INTRODUCTION The ECHELON-2 trial for newly diagnosed CD30+ peripheral T-cell lymphomas (PTCL) demonstrated superior overall survival with brentuximab vedotin plus chemotherapy (BV-CHP) compared to CHOP. However, total enrollment was restricted to only 30% of patients with non-anaplastic large cell lymphoma (ALCL) histologies and was not powered to analyze survival benefits in this cohort. Thus, the benefit of BV-CHP in non-ALCL patients remains less clear. Adding to this uncertainty, CHOP plus etoposide (CHOEP) remains a standard regimen for many non-ALCL PTCL histologies for patients <60 years of age. Which of these three regimens offers superior outcomes for patients with CD30+ non-ALCL PTCL remains to be determined, is a critical knowledge gap in this area, and could meaningfully inform the management of these patients. METHODS We conducted a retrospective analysis of chemotherapy-naïve CD30+ (≥1%) PTCL from 7 centers in the United States. Histologies were limited to PTCL-NOS and PTCL with a T follicular helper phenotype (PTCL-TFH). Frontline regimens were defined as BV-based (BV-CHP), etoposide-based (CHOEP/EPOCH), novel-CHOP (CHOP/CHOEP + novel drug on a clinical trial), or CHOP. CD30 was considered positive if any expression was reported, and when available, stratified as ≥10% or <10% of the total lymphocyte population. RESULTS The CD30+ PTCL cohort consisted of 194 patients with a median age of 68 years at diagnosis and a male (65%) predominance. Nodal PTCL-TFH (65%) was the most common histology. Most had stage III-IV disease (89%) with a high-intermediate to high-risk IPI score of 3-5 (54%). 18% had an ECOG of ≥2, 45% had ≥2 extranodal sites, and 43% had bone marrow involvement, although biopsies were not performed in all patients. CD30 expression in ≥10% of malignant T cells was observed in 55% of all quantitatively reported cases. Frontline therapy consisted of BV-based (36%), etoposide-based (30%), CHOP (27%), and novel-CHOP (7%). Baseline characteristics and CD30 expression were similar between treatment groups. The ORR was 72% (64% CR, 8% PR), with no differences observed by treatment or histology. On multivariate analysis (MVA), a high LDH was associated with lower CR (OR 2.84, p=0.003). For the patients who demonstrated a CR to frontline therapy, 61% underwent ASCT. With a median follow-up of 26.1 months (IQR 12.3-51.6), the median PFS and OS were 11.4 (9.8-14.2) and 47 (32-60.3) months, respectively. The 2-year PFS and OS were 34.9% (28.1-41.7) and 62% (54.5-68.6), respectively. PFS and OS were similar for PTCL-NOS compared to PTCL-TFH, and AITL fared similarly to non-AITL PTCL-TFH. By treatment, novel-CHOP demonstrated the most favorable PFS (median 41.9 months) and OS (median 68.1 months). Survival curves overlapped continuously with all other treatment regimens and was not statistically significant. For patients <60, PFS and OS were equivocal with BV-based (n=17) compared to etoposide-based (n=26) regimens. On MVA, stage III/IV disease conferred an inferior PFS (HR 2.00, p=0.018) as did an IPI score of 3-5 for OS (HR 2.15, p=0.001). Neither histology nor frontline treatment impacted PFS or OS. The chosen frontline treatment also had no survival impact in key subgroup analyses including patients <60 (n=56) or with CD30-expression ≥10% (n=43). For patients with CR to frontline therapy, ASCT demonstrated a significant PFS benefit (HR 0.59, p=0.028) but no statistically significant difference in OS benefit (HR 0.58, p=0.073). CONCLUSION These data provide valuable insight into the lesser-represented patient population from the pivotal ECHELON-2 trial. In this cohort of CD30+ (≥1%) non-ALCL PTCL, there was no clearly superior standard frontline regimen. The number of patients with quantitively reported CD30 expression was too small for definitive conclusions in the ≥10% CD30+ cohort and retrospective pathology review is ongoing. ASCT for patients in CR offered superior outcomes, supporting this strategy regardless of the frontline regimen, recognizing the limitations of non-randomized, retrospective analyses. Novel-CHOP regimens demonstrated encouraging survival, and clinical trials should maintain priority over standard regimens for patients with CD30+ (1-10%) PTCL-NOS and PTCL-TFH.

Abstract Introduction: Langerhans Cell Histiocytosis (LCH) is a rare histiocytic neoplasm, with approximately 90% of patients exhibiting alterations in the MAPK pathway. BRAF and MEK inhibitors have shown promising results in treating MAPK pathway-altered LCH. However, treatment interruptions due to adverse effects are common, and limited access to targeted therapies complicates care globally. While chemotherapy remains a common treatment for LCH, the outcomes for patients with MAPK pathway-altered LCH specifically receiving chemotherapy are still unclear. Methods: This multi-institutional international retrospective cohort study analyzed adult patients with BRAF or MAP2K (gain-of-function, GOF) altered LCH that were consecutively seen at Mayo Clinic, MN, AZ, and FL, University of Alabama at Birmingham, and Peking Union Medical College Hospital in China between 2007 and 2024. All patients who were included in this study were treated with chemotherapy, and those who have received targeted therapies or other modalities of frontline treatment were excluded. All time-to-event analyses were performed from the frontline therapy initiation, using the Kaplan-Meier method. Progression-free survival (PFS) included death and progression as events and was measured from the time of treatment initiation. The response assessment was based on radiographic evaluation in accordance with the most recent Histiocyte Society consensus guideline. Risk organ involvement was defined as disease involving the liver, spleen, bone marrow or central nervous system. Results: A total of 63 patients with LCH were included. The median age of the population was 34 years (range: 27-43), and males were 59%. Risk organ involvement was seen in 44 (70%) of patients and multisystemic LCH was observed in 48 (76%) patients. Among the 63 patients, BRAF gain-of-function alterations were observed in 79%, MAP2K mutations in 19%, and BRAF fusions in 2%. Of the BRAF gain-of-function alterations, BRAFV600E mutation was seen in 64% patients and [p.N486_P490del] deletion in 36%. There was no significant difference in organ involvement (single-system versus multisystem) or risk organ involvement between patients with BRAF and MAP2K alterations. All 63 patients received systemic therapy with chemotherapy and the regimens included Cytarabine (n=43), Cladribine (n=5), Etoposide (n=1), Methotrexate (n=1), and combined Methotrexate and Cytarabine (n=13). The median follow-up for the entire cohort was 3.8 years (range 3.2–5.0 years), with similar durations observed in patients with single-system vs. multisystem involvement and those with risk-organ involvement vs. no risk-organ involvement. The overall response rate among patients who received chemotherapy was 89%, with complete responses in 15 patients (26%) and partial responses in 40 patients (64.5%). The median progression-free survival (PFS) for the entire cohort was 2.61 years (95% CI: 2.06–NA). The 3-year PFS did not significantly differ based on risk organ involvement: 50.6% (95% CI: 36–71) for patients with risk organ involvement versus 47.4% (95% CI: 28–81) for those without, p=0.52. Patients with single-system disease experienced longer PFS compared to those with multisystem disease; the 3-year PFS was 80.2% (95% CI: 58.7–100) versus 42.2% (95% CI: 29–61.5), respectively, p=0.04. Conclusions: Our results indicate that LCH patients with a GOF alteration in the MAPK pathway derive significant clinical benefit from chemotherapy, achieving deep and durable responses. Therefore, patients should not be excluded from treatment due to the absence of targeted therapies, as they can still attain substantial responses and clinical improvement with chemotherapy, even in the context of MAPK pathway-driven disease.