Thanarajasingam, Gita

7075 Background: Hepatosplenic T-cell lymphoma (HSTCL) is a rare, aggressive peripheral T-cell lymphoma arising primarily from γδ T-cells. It carries a poor prognosis and resists conventional chemotherapy. Most reports on HSTCL are case-based. This study comprehensively analyzes a large cohort, evaluating treatment strategies and survival outcomes. Methods: This retrospective study included patients (pts) with pathologically confirmed HSTCL diagnosed between 2000-2024, consecutively seen at Mayo Clinic MN. Clinical, pathological, genomic, and treatment-related data were extracted when available. Descriptive statistics were used to summarize baseline characteristics. Time-to-event analyses, including Kaplan-Meier estimates, median overall survival (OS), and survival time estimates were conducted from the date of diagnosis. Results: A total of 20 patients with newly diagnosed HSTCL were included, with a median age of 57 years (range: 35-71). The cohort was predominantly male (70%) and non-Hispanic (93%). Molecular data was available for five patients, revealing abnormalities in STAT5B, MLL3 deletion, TP53, EZH2, TERT, and NF1 E291D . The median follow-up was 27.6 months (m) with a median OS of 17.6 m (95% CI: 11.2 - NA). First-line treatment was anthracycline-based in 68% of pts and non-anthracycline-based in 32%, with higher response rates in the latter group (50% vs.83%). Although non-anthracycline regimens showed a trend toward improved 3-year OS (100% vs. 29%) the difference was not statistically significant (p = 0.16). Achieving a complete response to first-line therapy was also associated with a trend towards a better 3-year OS compared to refractory disease (80% vs. 50%, p = 0.17). Most pts (79%) underwent hematopoietic stem cell transplant (HSCT), primarily allogeneic, with only one receiving autologous HSCT. First-line therapy before HSCT was evenly distributed between anthracycline (55%) and non-anthracycline (45%) regimens. HSCT recipients had significantly higher 3-year OS than non-recipients (83% vs. 33%, p = 0.017). Notably, the patient with a TP53 mutation has remained in remission for over a year post-allogeneic HSCT. Conclusions: HSTCL predominantly affects younger pts, with nearly half dying within a year. Allogeneic HSCT, rarely used in other NHL subtypes, improved survival. Non-anthracycline regimens and achieving CR trended toward better outcomes. Our study, leveraging a sizable cohort, highlights the need for targeted research and novel therapies to improve HSTCL management. Summary of survival outcomes in HSTCL. Characteristics Median OS (y) 3-Year OS (95% CI) 1.48 [0.93- NA] 46% [0.26 - 0.81] Transplant Transplant NA [NA - NA] 83% [0.58 - 1.00] No Transplant 1.02 [0.93 - NA] 33% [0.07 - 1.00] Treatment Anthracycline Based 1.02 [0.36 - NA] 29% [0.11 - 0.73] Non-Anthracycline Based 4.61 [NA- NA] 100% [1.00 - 1.00]

7052 Background: Secondary central nervous system lymphoma (SCNSL) is a rare but serious complication that occurs in 2-10% of patients (pts) with diffuse large B-cell lymphoma (DLBCL). The CNS-International Prognostic Index (CNS-IPI) is a validated tool used to assess the risk of CNS relapse. However, with advancements in molecular profiling and treatments, the predictors of SCNSL, including the predictive ability of CNS-IPI combined with other molecular markers and treatment regimens, have become uncertain. This study evaluates new prognostic markers for CNS relapse in DLBCL, focusing on cell-of-origin (COO), gene rearrangements, and treatment types. Methods: DLBCL pts enrolled from 2002-2015 in the Mayo Clinic and University of Iowa Lymphoma Molecular Epidemiology Resource were prospectively followed for incidence of CNS relapse. Pts with primary CNS lymphoma or CNS involvement at diagnosis, and pts treated with high-dose methotrexate containing regimens were excluded. COO classification (GCB vs non-GCB) was determined using Hans algorithm and/or NanoString data. Multivariate Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for predictors of SCNSL. Survival analysis was performed from time of DLBCL diagnosis using Cox proportional hazards model. Results: Among 1278 newly diagnosed DLBCL pts included (median age: 63 years; 43.6% female), SCNSL occurred in 46 (3.6%) pts. Pts with SCNSL were more likely to have intermediate/high CNS-IPI scores (80.4%) than pts without SCNSL (63.9%, p=0.02). The 3 yr SCNSL incidence was 0.016 (0.008-0.0033) in low CNS-IPI vs 0.043 (0.031-0.0060) in high CNS-IPI. Those with SCNSL were significantly more likely at baseline to have non-GCB COO (56.3% vs. 36.5%, p=0.02), and advanced stage (76.1% vs. 59.9%, p=0.03) compared to those without SCNSL. The incidence of SCNSL was not influenced by MYC, BCL2, or BCL6 rearrangements, nor by treatment with R-CHOP, R-EPOCH, or other immunochemotherapy regimens. MVA showed that intermediate CNS-IPI (HR 2.32, 95% CI 1.09-4.92, p=0.029), high CNS-IPI (HR 3.59, 95% CI 1.49-8.62, p=0.004), and non-GCB COO (HR 2.19, 95% CI 1.08-4.42, p=0.0029) were independently associated with increased SCNSL risk. After a median follow-up of 12 years (IQR 9–15), overall survival (OS) was 52.1% for the cohort, with OS significantly worse for SCNSL pts (17.4% vs. 53.4%, p<0.001). Conclusions: This large cohort with extensive follow-up highlights the role of COO as an additional prognostic factor for SCNSL while reinforcing CNS-IPI’s prognostic value. Non-GCB COO pts had a higher risk of SCNSL even when adjusted by CNS-IPI risk. Despite advancements in management, SCNSL pts continue to have poor outcomes. Strategies to reduce the incidence of CNS relapse in high-risk pts require further investigation. MER CNS relapse hazard ratios (95% CI). Characteristics Hazard Ratio 95% CI P-Value CNS-IPI Group 0-1 Low Ref Ref Ref 2-3 Intermediate 2.32 1.09 - 4.92 0.029 4+ High 3.59 1.49 - 8.62 0.004 Cell of Origin* GCB Ref Ref Ref non-GCB 2.19 1.08 - 4.42 0.029 Double Hit* non-DHL Ref Ref Ref DHL 1.08 0.14 - 8.3 0.941 Not Done/Missing 1.38 0.76 - 2.51 0.297 Double Expressor* Negative Ref Ref Ref Positive 2.36 0.71 - 7.85 0.162 Not Done/Missing 1.91 0.89 - 4.08 0.097 IC Group* R-CHOP R-EPOCH Ref 1.63 Ref 0.71 - 3.74 Ref 0.249 Other IC 1.18 0.57 - 2.46 0.660 Any EN Involvement* No Ref Ref Ref Yes 0.98 0.51 - 1.88 0.946 Albumin Group* >=Normal Ref Ref Ref <Normal 1.70 0.75 - 3.85 0.201 Head & Neck Involvement* No Ref Ref Ref Yes 0.35 0.048 - 2.63 0.310 *Adjusted by CNS-IPI risk group.

Abstract Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma involving the brain, cerebrospinal fluid, or retina/vitreous without systemic involvement. Induction with high-dose methotrexate (HD-MTX) followed by consolidation with autologous stem cell transplant (auto-SCT) has become the standard treatment paradigm for most patients. However, limited data are available regarding the efficacy of a maintenance approach with HD-MTX. Herein, we retrospectively reviewed the characteristics and outcomes of 148 patients diagnosed with PCNSL between October 2010 and June 2022, who underwent HD-MTX–based induction therapy followed by either auto-SCT consolidation (n = 70) or HD-MTX maintenance therapy (n = 37). At a median follow-up time of 4.5 years, the progression-free survival (PFS) was 8.3 years and the overall survival (OS) was not reached. Compared to patients who underwent auto-SCT, patients who received maintenance HD-MTX had a higher median age at diagnosis of 72 vs 62 years and a trend toward higher proportion of patients being Eastern Cooperative Oncology Group 2 or higher (41% vs 29%). At 5-years postinduction treatment initiation, the PFS rates in the auto-SCT cohort and HD-MTX maintenance cohort were 74.6% and 72.6%, respectively, and the OS rates were 76.0% and 82.4%, respectively. Overall, there was no significant difference in PFS or OS based on postinduction management strategy. Our data suggest that maintenance HD-MTX may be a reasonable, time-limited treatment strategy for patients with PCNSL responding to initial induction therapy.

PURPOSE Lymphomas are a heterogeneous group of diseases that develop in individuals of all ages and have variable prognoses. Improved survival resulting from therapy advances has led to the emergence of diverse late effects. Although several (US)–based organizations have developed survivorship guidelines, the distinct features of lymphoma subtypes and diverse therapies used raise concerns regarding their applicability to lymphoma survivors. We compared survivorship recommendations (outside primary disease monitoring) between US clinical guidelines. METHODS We extracted information from 17 guidelines from five US-based organizations: ASCO (n = 11), American Cancer Society (n = 1), Children's Oncology Group (n = 1), Center for International Blood and Marrow Transplant Research (n = 1), and the National Comprehensive Cancer Network (n = 3). Guidelines were evaluated to determine whether they offer recommendations on physical effects , psychosocial and quality of life ( QOL ), and health promotion and prevention . Comparisons were focused on second primary malignancy, cardiovascular complications, and vaccination. RESULTS Survivorship recommendations on physical effects and psychosocial and QOL mainly differ in the timing and approaches for screening. Vaccination recommendations were primarily derived from other cancer populations. Identified research gaps were a lack of understanding of the risk of late effects across lymphoma subtypes, the role of social determinants of health in survivorship, and the lack of a survivorship care model that integrates lymphoma subtypes and treatment exposures. CONCLUSION This study raises awareness about the complexity and challenges of managing survivors under the umbrella diagnosis of lymphoma. The inconsistency and incompleteness of existing guidelines may lead to suboptimal survivorship care. We propose expert-based research priorities to address gaps and unmet needs to help develop risk-based follow-up recommendations to optimize survivorship care for lymphoma survivors.

Background: Splenic marginal zone lymphoma (SMZL) is a rare indolent disease with a median overall survival (OS) of more than 10 years, although a proportion of patients may develop aggressive histology transformation. In a previous report from this large, international dataset, the 10-year cumulative incidence of transformation was 17% (95% 13-21) and in another study of 186 patients, the 10-year cumulative incidence was 14%Click or tap here to enter text.. In this report, we focus on risk factors for transformation as well as clinical characteristics and outcomes of transformed SMZL (tSMZL). Patients and methods: Adults diagnosed with SMZL in 2000-2018 were identified through regional or nationwide population-based registries or from hospital registries. Only patients likely to have SMZL as defined by Matutes et al. were included. Those with discordant lymphoma and/or transformation at diagnosis were excluded. Medical records were reviewed by local clinicians with experience in hematology/oncology, and detailed information on clinical characteristics, treatment lines, and outcomes was collected. Only histologically confirmed high-grade transformations (HT) were included. OS was defined as the time from transformation to death or censoring at last follow-up. Additional analyses stratified by treatment exposure prior to HT and treatment of HT were conducted. Multivariable Cox analyses were performed to determine clinicopathological features associated with transformation and OS. Results: Out of 940 patients with SMZL, 111 developed HT during a median follow-up of 9.1 years. The median time from diagnosis to HT was 3.4 years with an interquartile range of 1.6-7.4 years. Median age at HT was 71 years. Patients with HT shared similar baseline characteristics to those without in terms of age at diagnosis (66.4 vs 67.6), f:m ratio (1.5 vs 1.1) and ECOG ³2 (7.2% vs 7.4%). The 5-yr OS from the time of HT was 42% (CI 95%, 32-54). Of the 111 patients with tSMZL, a complete treatment history from SMZL diagnosis until HT was available for 88 included in the following analyses. By the time of HT, 46 had not received any prior systemic therapy (37 only splenectomy, 9 no therapy), 6 patients had received rituximab alone or combined with splenectomy, and 36 patients had received chemotherapy alone or as part of combined modality treatment. In a uni- and multivariable models for HT, we assessed age, treatment at diagnosis, sex, extra-hilar lymphadenopathy, and extranodal involvement. In both the uni- and multivariable model, age &gt;70 (HR 1.9, 95% CI: 1.1-3.4), immediate treatment including splenectomy (HR 2.0, 95% CI: 1.05-3.6), and extra-hilar lymphadenopathy (HR 1.9, 95% CI: 1.1-3.3) were associated with higher HT hazard, while extranodal involvement (HR 0.23, 95% CI: 0.06-0.84) was associated with a lower HT hazard. At the time of first-line treatment, multivariable analysis revealed similar results and with no association between risk of transformation and treatment strategy (i.e splenectomy alone, rituximab monotherapy or chemotherapy with /without rituximab or splenectomy, and other). At the time of HT, patients who had been previously treated with chemotherapy had an inferior 5-year OS of 24% (95%CI: 13-44%) versus 54% (95%CI: 41-71%) for those who had not received chemotherapy prior to HT. In contrast, there was no difference in the survival of patients that transformed less than or more than 24 months from diagnosis with 5-year OS after HT of 35% (95%CI 20-60%) and 45% (95%CI, 33-61%) respectively. In a multivariable Cox regression analyses of age at time of HT, sex, time since last treatment &lt;24 months, chemo-exposure in previous treatment lines and anthracycline-containing therapy (+/-R) at the time of HT, only prior chemo-exposure was borderline associated with poorer OS (HR 1.8, 95%CI: 0.9-3.5). Conclusion: Patients with SMZL face a notable risk of developing tSMZL over time. Patients in need of immediate treatment at first SMZL diagnosis, age &gt;70 and extrahilar lymphadenopathy had a higher risk of tSMZL and outcomes at the time of HT were poor if patients had been exposed to prior chemotherapy after adjustment for age, sex, and time since last treatment.

Background: Indolent non-Hodgkin lymphomas (iNHL) are incurable and disproportionately affect adults age &gt;65 in whom frailty and functional impairment can impact disease management. The Vulnerable Elders Survey (VES-13) is a 13-item screening tool that incorporates age, self-rated health, physical function limitations, and functional disabilities to identify vulnerable older community-dwelling adults. Adults with a VES-13 score of &gt;3 have a fourfold increased risk of death or functional decline over 2 years as compared to adults with a score &lt;3 (Saliba et al, JAGS 2001). Our team previously showed that VES-13 &gt;3 was associated with a higher risk of 1-year mortality in NHL (OR 3.26, 95% CI 2.15-4.96, Fama et al, ASH 2019), including in adults age &lt;65. In this study, we determined whether VES-13 scores &gt;3 were associated with quality of life (QOL) changes in adults with iNHL across the age spectrum. Methods: We used the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study to identify adults enrolled from 2015-2020 with grade 1-3A follicular and marginal zone lymphoma (FL, MZL) who completed the VES-13 at enrollment and QOL surveys at enrollment and follow-up. The LEO Cohort Study enrolls participants within 6 months of diagnosis and collects information on disease status, QOL, health behaviors, and patient-reported functional assessment. For this analysis we included QOL measured using the Functional Assessment of Cancer Therapy-General (FACT-G) at years 1 and 2 post-enrollment. The FACT-G total score was the sum of 4 subscales (range): physical (PWB, 0-28), social/family (SFWB, 0-28), emotional (EWB, 0-24), and functional (FWB, 0-28) well-being. A higher FACT-G total score (range 0-108) indicated better overall QOL. VES-13 scores ranged from 0 (lowest risk for death or decline) to 10+ (highest risk). Generalized linear mixed models evaluated changes in QOL from baseline based on VES-13 score &gt;3 (vulnerable) vs &lt;3 (non-vulnerable), within groups by age at enrollment &gt;65 and &lt;65. Results: Our study included 1,186 participants: 42% age &gt;65, 54% female, 84% non-Hispanic White, 10% Hispanic, 3.3% Black, and 1.4% Asian/Pacific Islander. Most (68%) were diagnosed with FL. FLIPI was high risk for 20%, and MALT-IPI was high risk for 23%. In the VES-13 &lt;3 group, the mean (SD) baseline FACT-G total score was 86.5 (12.0), PWB 21.0 (3.5), SFWB 24.3 (4.3), EWB 18.8 (3.7), and FWB 22.3 (4.9). In the VES-13 &gt;3 group, the mean (SD) baseline FACT-G total score was 70.4 (16.5), PWB 15.4 (5.6), SFWB 22.3 (5.5), EWB 17.5 (4.5), and FWB 15.3 (6.4); all significantly lower than the VES-13 &gt;3 group (all p&lt;0.01). In adults &lt;65, 63 (9%) had a VES-13 &gt;3, which was associated with a significant improvement from baseline in PWB at years 1 and 2 when compared to VES-13 &lt;3 (changes in baseline PWB were 2.1, 2.9 for VES-13 &gt;3 vs 0.2, 0.1 for VES-13 &lt;3, all p&lt;0.05). Similarly, we observed improvement in FWB from baseline at years 1 and 2 in the VES-13 &gt;3 vs &lt;3 group (2.4, 2.9 vs 0.4, -0.1, respectively all p&lt;0.05). The VES-13 &gt;3 group had a decline in their EWB at 1 year vs the VES &lt;3 group (-0.5 vs 1.2, respectively, p=0.003). At year 2, total FACT-G improved from baseline in the VES-13 &gt;3 group (5.6 for VES-13 &gt;3 vs -0.5 for VES-13 &lt;3, p=0.002). SFWB changes from baseline did not differ between groups. In adults &gt;65, 83 (17%) had a VES-13 &gt;3, which was associated with a significant improvement from baseline PWB (1.3, 1.5 for VES-13 &gt;3 vs. 0.1, -0.1 for VES-13 &lt;3), FWB (3.3, 2.2 for VES-13 &gt;3 vs. 0.5, 0.1 for VES-13 &lt;3), and total FACT-G score (5.2, 3.4 for VES-13 &gt;3 vs. 1.0, -0.4 for VES-13 &lt;3) when compared to VES-13 &lt;3 at years 1 and 2 (all p&lt;0.05). SFWB and EWB changes from baseline did not differ between groups. While there was improvement from baseline PWB and FWB in the VES-13 &gt;3 group, QOL scores across all subscales remained below the VES-13 &lt;3 group in the study period for both age groups. Statistical significance was maintained in models adjusted for baseline characteristics, including initial treatment strategy (observation, systemic, vs local) for both age groups. Conclusion: Although the vulnerable group reported worse QOL throughout the study period compared to the non-vulnerable group, survivors in the vulnerable group saw greater improvement in their physical and functional well-being at 1- and 2-years post-diagnosis. Additional analyses are underway to identify drivers of improvement in physical and functional well-being in vulnerable adults diagnosed with iNHL.

Background: Immunochemotherapy is the current standard-of-care frontline therapy for diffuse large B-cell lymphoma (DLBCL). Our group previously reported that addition of the mTOR inhibitor everolimus to R-CHOP resulted in excellent efficacy in the Alliance N1085 trial (Witzig TE et al, Blood Cancer J, 2017, 7(6):e576), with 23 of 24 patients achieving event-free survival at 24 months (EFS24), supporting further investigation of PI3K/mTOR targeting in DLBCL. New insights into molecular classification of DLBCL suggest that multiple genetic subtypes of DLBCL (eg, MCD, BN2, ST2, and EZB per LymphGen classification) may be susceptible to PI3K/mTOR targeting. Therefore, we conducted a phase 1/1b trial to investigate the safety and efficacy of combination therapy with a novel PI3K inhibitor parsaclisib and standard immunochemotherapy. Methods: Adult patients with newly diagnosed DLBCL were eligible if any of the following was present: 1) non-GCB subtype per the Hans algorithm; 2) protein expression of either MYC (≥40%) or BCL2 (≥50%) by immunohistochemistry; or 3) MYC rearrangement by FISH. Patients with high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements were also eligible. Phase 1 followed a 3+3 design to determine the maximum tolerated dose (MTD) of parsaclisib (plus R-CHOP) to be used in Phase 1b (dose expansion). The primary efficacy endpoint in phase 1/1b was complete response (CR) rate by PET. A polatuzumab vedotin (Pola) safety lead-in cohort was added later to explore the safety and efficacy of parsaclisib (at MTD) plus Pola-R-CHP. Results: From July 2020 to May 2023, 50 patients were enrolled; 1 patient withdrew consent before study treatment and was excluded from this analysis. Nine patients were treated in Phase 1, 33 in Phase 1b, and 7 in the Pola cohort. The median age at diagnosis was 66 years (range 20-86), and 20 (41%) were female. Two (4%) patients had ECOG PS ≥2, 26 (53%) had elevated LDH, 19 (39%) had &gt;1 extranodal site, 37 (76%) had stage III/IV, and 25 (51%) had high-intermediate or high-risk International Prognostic Index (3-5). 23 (47%) had non-GCB subtype, 23 (46.9%) had MYC or BCL2 single expression, 21 (42.9%) had MYC/BCL2 double expression, and 6 (12%) had MYC rearrangement (2 with BCL2 and/or BCL6 rearrangements). In Phase 1, 3 patients were treated at dose level 1 (parsaclisib 20 mg QD, d1-10) and 6 at dose level 2 (parsaclisib 20 mg QD, d1-14). No dose limiting toxicity was observed. Therefore, dose level 2 for parsaclisib was the MTD and was used in Phase 1b. In the Pola cohort (n=7), only 1 of 6 evaluable patients experienced significant toxicity (grade 3 diarrhea). Among all 49 patients, the most common treatment-related adverse event (TRAE) of any grade included neutropenia (83.7%), thrombocytopenia (79.6%), leukopenia (77.6%), lymphopenia (71.4%), anemia (71.4%), nausea (63.3%), fatigue (40.8%), peripheral sensory neuropathy (36.7%), constipation (24.5%), and diarrhea (22.4%), and the most common grade ≥3 TRAE included neutropenia (71.4%), leukopenia (69.4%), lymphopenia (49.0%), thrombocytopenia (20.4%), anemia (16.3%), febrile neutropenia (6.1%), and diarrhea (6.1%). In Phase 1/1b (n=42), the overall response rate (ORR) to parsaclisib plus R-CHOP was 97.6%, and the CR rate was 90.5%. After a median follow-up of 28.5 months (95% CI 27.7-32.7), the estimated 2-year progression-free survival (PFS) rate was 84.6% (95% CI 73.9-96.8), and the estimated 2-year overall survival (OS) rate was 95.1% (95% CI 88.7-100.0). In the Pola cohort, the ORR to parsaclisib plus Pola-R-CHP was 100% and the CR rate was 100%. After a median follow-up of 15.6 months (95% CI 13.5-NE), 1 patient had disease relapse at 11.95 months, and all patients were alive. Conclusions: Addition of the PI3K inhibitor parsaclisib to R-CHOP or Pola-R-CHP immunochemotherapy is considered safe in patients with newly diagnosed DLBCL. Combination of parsaclisib and standard immunochemotherapy resulted in high ORR and CR rate and encouraging preliminary PFS and OS outcomes patients with high-risk DLBCL. These data support further investigation of PI3K/mTOR targeting in newly diagnosed DLBCL in future trials.

Introduction: Phase I trials are designed to evaluate the safety and tolerability of new treatments. Review of adverse events (AEs) experienced by trial participants is a critical aspect of these early phase trials. Current practice for safety and tolerability data collection is for clinicians to evaluate AEs using the Common Terminology Criteria for Adverse Events (CTCAE). Past work has demonstrated that clinicians may miss or underreport symptomatic AEs. The Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE) is an item library of questions for patients to self-report symptomatic AEs in clinical trials that is complementary to the CTCAE. PRO-CTCAE offers a patient-centric method for capturing symptomatic AEs, which may be missed or underreported by clinicians. The PRO-CTCAE library includes questions using patient friendly terms to assess frequency, severity, and interference of symptomatic AEs on 0-4 verbal descriptor scales (e.g., severity is rated by patients as none, mild, moderate, severe, or very severe). The goal of the current work was to demonstrate how to incorporate AE information from PRO-CTCAE and CTCAE into a Phase I dose review report. Methods: We used data from a Phase I clinical trial of patients with relapsed or refractory acute myeloid leukemia. Therapy was administered on 28-day cycles. Patients completed questionnaires on an electronic device on days 1, 8, 15, and 22 of the first cycle of treatment. Through iterative feedback from clinicians and statisticians, we developed an example dose review report. The report summarized data for one dose level in which 4 patients were treated. These 4 patients comprised the first patient cohort enrolled in the available Phase I clinical trial. The report was intended to be representative of the type of report that would be reviewed to make a decision about the next dose level for a new cohort of patients. Results: The final dose review report included narratives for each patient generated by the statistical team based on patient-reported and physician-graded AEs in cycle 1, tabular summaries integrating CTCAE and PRO-CTCAE, and novel graphical presentation of PRO-CTCAE and CTCAE, including swimmer plots and butterfly plots for symptoms listed as dose limiting toxicity criteria. In this cohort, 3/4 (75%) patients had at least one grade 3+ AE, as assessed by CTCAE, and 4/4 (100%) patients had at least one score 3 symptomatic AE, as assessed by PRO-CTCAE. All 4/4 (100%) patients had at least one reported symptom on the PRO-CTCAE that was not captured by CTCAE or was reported at a lower grade by CTCAE. Multiple versions of the example dose review report were presented to the study team and iterative feedback was solicited from clinicians and statisticians. Feedback highlighted the usefulness of narratives and patient-level graphical displays. Narratives within the dose review report were refined to focus on treatment emergent AEs, minimizing text and succinctly presenting baseline symptoms where relevant. Symptom-level graphics of combined PRO-CTCAE scores and CTCAE grades were preferred over graphics consolidating data for multiple symptoms. Final graphics and report will be presented. Conclusions: We demonstrated that PRO-CTCAE, which captures patient-reported symptoms, complements traditional AE reporting and that reporting PRO-CTCAE and CTCAE jointly in a Phase I dose level report can provide a more complete picture of safety and tolerability in the Phase I setting.

Background: Physical function (PF) is an important outcome that can inform cancer treatment tolerability from a clinical and regulatory perspective. PF can be assessed through different modalities: patient-reported (PRO), clinician-reported (ClinRo), performance tests (PerfO), and digital sensors (wearables). No standard approach for PF measurement has been defined, and each modality bears unique implementation challenges. The Integrating 4 Measures to Assess Physical Function study (In4M, NCT05214144) characterized the performance of these PF modalities in patients receiving cytotoxic chemotherapy, with a goal of guiding an assessment strategy in future cancer trials. Here we present feasibility results of the In4M study in patients with lymphoma. Methods: In4M is a prospective observational study with longitudinal PF assessment of PROs, ClinRo, PerfO, and wearable sensor data for over 9 months in patients initiating chemotherapy for lymphoma or breast cancer at Mayo Clinic and Yale University. Patient-reported PF was assessed using several validated ePRO instruments, ClinRo utilized clinician-reported Eastern Cooperative Oncology Group (ECOG) performance status, PerfO was measured via 6-minute walk test (6MWT), and digital sensor data was obtained from a wearable (Fitbit) provided to all participants. We evaluated the feasibility of implementing these PF modalities through compliance outcomes and a study-specific exit survey. Descriptive statistics included medians and interquartile ranges (IQR) for continuous variables and frequencies for categorical variables. We used a mixed model to estimate mean number of Fitbit compliant days per week. Results: Among 66 patients with lymphoma in the study (median age was 57 years; 52% were male), 90% self-reported as White, 4.9% as Black, 1.6% as Asian, 1.6% as American Indian or Alaska Native, and 1.6% as multiple races. Ethnicity was reported as non-Hispanic/Latino by 93% of patients. Education status was reported as more than high school by 92% of patients, and 49% reported full-time employment at time of enrollment. The overall ePROs completion rate was 80.7% for the entire study period. Baseline ePRO completion rate was 93.9%. Completion rate while undergoing chemotherapy was 91.3% and 75.4% in the post-treatment follow-up. The median time to complete ePROs was 4.1 minutes (IQR 2.8-5.9), ranging from 3.1 minutes for surveys with 37 questions to 5.6 minutes for surveys with 55 questions (survey length varied by timepoint). The baseline 6MWT was completed by 91% of patients. The most common reasons for not completing the baseline 6MWT were: patient refusal (50%, 3/6), patient not physically present (33%, 2/6), and unable to complete due to fatigue (17%, 1/6). The 3-month 6MWT was completed by 66% (40/61) of patients, with the most common reasons for missingness being: patient not physically present (38%, 8/21) and unable to complete due to fatigue (14%, 3/21). When considering the days when Fitbit was used, the median wear time was 21.3 hours (IQR 18.9-22.5) per day. The proportion of compliant days (&gt;10 hours of wear time during waking hours) was 53% (IQR 20-84). The median of participants' average compliant days per week was 5.4 (IQR 4.3-6.1) days/week after enrollment, with a slight downward trend over time (-0.017 compliant days per week [95% CI: -0.021, -0.012, p &lt;0.001] over each consecutive week in the study). The exit survey was completed by 39 (59%) patients. Most participants (85%) indicated they did not find the ePRO surveys burdensome to complete. Using the Fitbit (charging and syncing) was found to be manageable by most patients (87% and 84%, respectively). 60.8% of patients did not find the wearable bothersome to use, while the main themes reported by the remaining patients were related to the operation of the wearable itself (functions, small text size, forgetting login information) or discomfort (band material, wearing at night). Conclusion: Multi-modal assessment of PF with PRO, ClinRo, PerfO and wearable sensor data in patients with lymphoma undergoing treatment is feasible. Designing lymphoma therapeutic trials that incorporate at least one PF assessment modality, or assessment with a parsimonious combination of modalities, is achievable and may yield valuable insights into treatment tolerability for clinical and regulatory purposes.