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Background: Although advanced stage cHL typically has excellent disease outcomes, 20-30% of patients (pts) experience treatment failure. In addition, decision-making is challenging given varying treatment options and incomplete prognostic data across the disease course. Pre-treatment factors, such as those incorporated into the Advanced Stage Hodgkin Lymphoma International Prognostication Index (A-HIPI), predict 5 year (y) overall survival (OS) and progression-free survival (PFS) (Rodday JCO 2023). Other than interim PET (iPET) results, it is unknown what factors influence cHL disease states mid-therapy. Using multistate modeling (MSM) and individual pt data from the HoLISTIC Consortium, we refined prognostication across the cHL disease course, specifically assessing the relationships between A-HIPI, iPET and end of treatment (EOT) response, and whether the A-HIPI and iPET provide independent prognostic information. Methods: We analyzed 1240 pts aged 18-65y with newly diagnosed Stage IIB, III or IV cHL treated on 2 advanced stage PET-adapted trials (RATHL, SWOG0816). All pts first received 2 cycles of ABVD; those with a negative iPET (Deauville score (DS) ≤3) received ABVD or AVD, and those with a positive iPET (DS >3) received BEACOPP. In contrast to other methods, MSMs incorporate multiple disease states into one model, account for censoring and competing risks, and estimate transitions between disease states using different covariates. Our MSM had 6 states: diagnosis, negative iPET, positive iPET, EOT non-progression (e.g., DS ≤ 3), treatment failure, and death. Treatment failure included progression or relapse. All pts start at the diagnosis state and can transition to other states without return to prior states. Transition states with <5 events were excluded. The MSM was estimated using a multivariable Cox model with censoring at 5y. Covariates were the 5y PFS A-HIPI (comprised of stage and continuous age, lymphocyte count and albumin), which was included for all transitions, and iPET, which was included for transitions from EOT non-progression and from treatment failure. Higher scores on the 5y PFS A-HIPI indicate lower risk of progression or death; the A-HIPI was modeled for a 1 standard deviation (SD) increase. We calculated probabilities of 5y treatment failure for 4 sample pts based on low (70) and high (85) A-HIPI scores, positive and negative iPET, and EOT non-progression. Results: Median age was 33y (Q1=25, Q3=45), 56% were male, 23% were stage IIB, 40% III and 37% IV, and mean A-HIPI was 77 (SD=7). Median follow-up was 75 months (Q1=53, Q3=92). At iPET, 80% (95% CI 78%, 83%) were negative and 16% (95% CI 14%, 18%) were positive. At EOT, 90% (95% CI 89%, 92%) were in the non-progression state. At 5y, 75% (95% CI 73%, 78%) were in the non-progression state, 16% (95% CI 14%, 19%) had experienced treatment failure, and 9% (7%, 11%) had died. Better A-HIPI scores (per SD) were associated with lower rates of transitioning from diagnosis to positive iPET (HR=0.80, p<0.01) and from positive iPET to treatment failure (HR=0.58, p=0.04). Better A-HIPI scores (per SD) were also associated with lower rates of transitioning from EOT non-progression to treatment failure (HR=0.78, p<0.01) and from treatment failure to death (HR=0.64, p<0.01), adjusting for iPET. Positive iPET was associated with an increased rate of transitioning from EOT non-progression to treatment failure (HR=1.90, p<0.01), adjusting for A-HIPI. The probability of 5y treatment failure for 4 sample pts was: 25% for low A-HIPI and positive iPET; 20% for high A-HIPI and positive iPET; 13% for low A-HIPI and negative iPET; and 12% for high A-HIPI and negative iPET. Conclusions: We created a novel MSM that refines prognostication across the cHL disease course by incorporating pre- and post-treatment factors (e.g., iPET) to estimate transitions to future disease states. Although the A-HIPI was developed using pre-treatment factors to predict 5y OS and PFS, we found that it was also associated with transitions to interim disease states, including iPET and EOT response. The A-HIPI and iPET each provided independent prognostic information, supporting the use of both in estimating cHL outcomes. Future analyses will develop clinical prediction models using MSMs that also incorporate varying frontline and salvage treatments and treatment-specific late effects, with the goal of providing individualized information across the disease course.

Background: Approximately20% of patients with follicular lymphoma (FL) will experience disease progression or death within two years of years (POD24) of immunochemotherapy (IC) (Casulo et al, JCO 2015). A proportion of patients with POD24 have histologic transformation (HT), which heightens the risk of lymphoma-related death (Freeman et al, Blood 2019). To clarify the impact of HT on prognosis in POD24, we analyzed data from the Lymphoma Epidemiology of Outcomes (LEO) Consortium of Real-World Evidence (CReWE) to compare differences in outcomes among patients with POD24 with retained FL histology versus POD24 with HT. Methods: This was a multicenter study among 8 academic cancer centers. Eligible patients hadgrade 1-3a FL at diagnosis between 2003 and 2022, with POD24 following first line IC treatment with BR, R-CHOP, or R-CVP. POD24 was defined as disease recurrence within 24 months of IC. Patients with prior lines of treatment for FL were excluded. Patients with HT at first line IC were excluded. Biopsy at POD24 was obtained at the discretion of the treating physician. Three groups of POD24 were defined: POD24 with biopsy-proven retained FL histology (POD24_FL), POD24 with biopsy-proven HT to aggressive lymphoma (POD24_HT), and POD24 either without a biopsy or indeterminate histology on biopsy (POD24_I). We evaluated second-line treatments at time of POD24. Survival probabilities from second-line treatment initiation were estimated by the Kaplan-Meier method. Results A total of1,122 patients with FL were screened and308 patients with POD24 were identified.Median age at POD24 was 58 years (IQR 50-65).Among available data, race and ethnicity was reported as 76% non-Hispanic White, 3% non-Hispanic Black/African American, 9% Hispanic/Latino (any race), and 1% other minorities. First line therapy was R-CHOP in45% (140/308), BR in 33% (102/308) and R-CVP in 21% (66/308). Most patients (52%) had biopsy-proven retained FL at POD24 (162/308); 30% had no biopsy or indeterminate histology at POD24 (94/308), and 17% had biopsy-proven HT at POD24 (52/308). In the POD24_HT group, 52% received R-CHOP and 21% received intensive salvage chemotherapy as second line therapy. Patients with POD24_FL and POD24_I had similar rates of salvage chemotherapy (21% and 18%), BR (13% and 18%), R-CHOP (19% and 24%), and targeted therapies (8% and 5%), respectively, at second line. Consolidative autologous stem cell transplant was more common in POD24_HT patients at 21% versus 16% in POD24_FL and 6% in POD24_I. Patients with POD24_HT had significantly worse overall survival (OS) compared to POD24_FL (ref), with a hazard ratio of 3.79 (95% confidence interval [CI] 2.46-5.84), even after adjusting for age, FLIPI score, and first-line IC treatment. At 5 years, patients with POD24_HT had OS of 31% compared with an OS of 71% for patients with POD24_FL. Patients with POD24_I had similar outcomes to those with POD24_FL (5-year OS 75% versus 71%, respectively). Event-free survival (EFS) was also significantly lower in POD24_HT compared to POD24_FL: At 2 years, EFS was 27% for POD24_FL (21-35%) and 10% for POD24 _HT (4-23%). At 5 years, lymphoma remained the leading cause of death among patients with POD24, with 20% probability of lymphoma-related death in those with POD24_FL (95% CI 14.2-27.8) compared to 53% probability of lymphoma-related death in patients with POD24_HT (95% CI 40.6-70.7). Conclusions: In our multicenter cohort, we identified remarkable differences between the two biopsy-demonstrated entities of POD24 (i.e., with and without HT). Patients without a biopsy or indeterminate histology had similar outcomes as those with POD24_FL. Patients withearlyrelapse of FL after first-line IC remain a heterogeneous group with poor outcomes and a heightened risk of lymphoma-related mortality particularly compared with nonPOD24 groups. Even with retained FL histology, patients with POD24 had 20% probability of lymphoma-related death within 5 years of second-line treatment initiation. We demonstrate that poor survival is driven in part, but not entirely, by HT. Despite most patients receiving appropriate aggressive treatment, those with POD24_HT represent a distinctly vulnerable population warranting further study in directed prospective studies of both FL biology and clinical trials.

Background: Due to recent advances, patients with follicular lymphoma (FL) have multiple treatment options with high response rates and durability. However, there is a gap in understanding how patient preferences influence treatment selection. To close this gap, we conducted a qualitative study using focus groups of adults with FL to understand their knowledge of treatment options, priorities, and decision-making process. We designed this study to inform the content of a planned discrete choice experiment in a larger population of patients with FL to better understand patient preferences and trade-offs around treatment delivery, side effects, outcomes, and quality of life. Methods: We conducted focus groups lasting 60-90 minutes, each with 3-5 participants recruited from the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study. The LEO Cohort Study is a multi-institutional prospective cohort study of newly diagnosed adults with non-Hodgkin lymphoma from July 2015 to present. Each focus group was co-led by two investigators (U.D. and M.T.) and conducted using Zoom video technology. Participants were asked to comment on their understanding about FL and available treatments, their ideal treatment, their decision-making process about prior therapies, and quality of life and side effects associated with treatment. We performed exploratory content analysis of participant understanding of FL and their treatment preferences. We will continue to conduct focus groups until we reach thematic saturation, which we anticipate will occur with one additional focus group. Themes from all focus groups were identified and agreed upon by both investigators (U.D. and M.T.) and were verified by additional investigators (J.D., M.L, M.H., B.K.L, C.C., M.M.). Results: To date, we conducted five focus groups with a total of N=21 participants (median age 60 [range 41-88], 66.7% female, 71.4% non-Hispanic White, 14.3% Hispanic, 9.5% Asian, 4.8% Black/Hispanic). We identified the following themes and representative quotes: 1) Holistic approach:Participants wanted their oncologists to view their care from a holistic perspective, discussing their individual priorities and options that would accommodate their fitness routine and ability to work. “[I wish] if doctors can consider not just the physical choices, but also the mental and emotional choices as well, the holistic person.” - Participant 13 “There's zero chance I can go back to working in the type of career where other people rely on me for things. I can't keep things straight.” - Participant 16 2) Ideal treatment:An ideal treatment would limit impact on fatigue, cognitive function, and have minimal toxicity to preserve quality of life and an active lifestyle. “I would say something that has minimal impact on daily life would be ideal and something that would make you feel better.” - Participant 6 3) Shared decision-making: Participants wanted to be better informed about available treatment options and often utilized second opinions to inform their decisions. “It helped to get the second opinion versus not. It would've been a completely different set of events.” - Participant 17 4) Treatment burden:Financial impact and effort required by patients to receive care (e.g., travel, number of office visits, and duration of therapy) were key factors in patient decision-making. “Part of my quality of life went down because I had to fight with my insurance company consistently, and we pay a lot of money.” - Participant 11 “Really explain the time options and calendarize the treatment and be more specific about the amount of time that you're going to spend at the hospital and the process.” - Participant 20 5) Representation: Minority participants raised concerns about not knowing if the available treatment data pertained to them. “[My end-goal would be] having an understanding of how the treatment is going to be for minority people. Many times the treatments are tested, they are not tested for minorities.” - Participant 21 Conclusions: The patient perspective is critical for treatment decision-making and education. People living with FL expressed a desire for a holistic and individualized approach to treatment decision-making that incorporated their lifestyle, minimized side effects, and limited overall treatment burden. These focus groups identified emerging themes that warrant further investigation for survivors with FL.

ABSTRACTDiffuse large B‐cell lymphoma (DLBCL) patients that fail to achieve a complete metabolic response with frontline immunochemotherapy have a poor prognosis. Genomic profiling has led to a broader understanding of the molecular drivers in DLBCL, but it is unknown how well current classifiers identify patients that will experience primary treatment resistance (PTR). Using whole exome and RNA sequencing data from newly diagnosed DLBCL patients, we evaluated the genomic landscape of PTR and compared it to that of non‐PTR DLBCL. We found a significant increase in the frequency of TP53 (34% vs. 15%, p = 0.005) and ARID1A mutations (21% vs. 7%, p = 0.007) in PTR cases, with pathway analysis further demonstrating a downregulation of TP53 and an increase in chromatin modifying pathways. These results suggest that TP53 and ARID1A may be key mediators of PTR and important pathways contributing to the poor outcomes. We found that the current molecular classifiers were unable to identify PTR cases at diagnosis. However, our newly identified high‐risk signature identified 46% of PTR cases at diagnosis. Overall, these results contribute to our understanding of the genomic landscape of patients with primary treatment resistance.

Abstract Progression of disease within 24 months of initial immunochemotherapy (POD24) is a negative prognostic factor for patients with follicular lymphoma (FL). There is no standard treatment after POD24. Assembling an academic-based cohort from the Lymphoma Epidemiology of Outcomes Consortium for Real World Evidence, we evaluated patterns of care and outcomes for 220 patients with FL with POD24 and retained FL histology. Therapy after POD24 was heterogeneous, with no treatment category accounting for >25% of the total. Among patients initially treated with bendamustine-rituximab, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) was the predominant second-line choice (48%). Among patients initially treated with R-CHOP, aggressive salvage therapy was the predominant second-line choice (38%). Overall response rate to therapy after POD24 was 64% (95% confidence interval [CI], 56-70); complete response rate was 39% (95% CI, 32-46). The median event-free survival for therapy after POD24 was 9.8 months (95% CI, 7.3-12.1); 5-year overall survival (OS) was 71% (95% CI, 65-78). OS was inferior for patients aged >70 years (hazard ratio [HR], 2.31; 95% CI, 1.27-4.20) and those with high-risk FL International Prognostic Index scores at diagnosis (HR, 2.10; 95% CI, 1.23-3.60). No treatment category stood out with more favorable results. Cause of death was predominantly lymphoma related. Patients with follicular histology at their POD24 event had a low cumulative incidence of transformation (1.1% at 5 years). Our study is among the largest cohorts describing contemporary patterns of care for patients with POD24, providing a focused data set useful for interpreting and designing prospective clinical trials in this population.

Abstract Background/Introduction Patients with ATTR-CM can have lower circulating TTR levels, which is associated with worsening of cardiac function and increased risk of cardiovascular mortality.[1] Acoramidis has been shown to reduce cardiovascular mortality and hospitalization, while increasing circulating TTR levels, in the ATTRibute-CM phase 3 study.[2] Purpose I. Evaluate serum TTR levels in participants (pts) receiving acoramidis vs those who received tafamidis in the placebo group in ATTRibute-CM at Month 30. II. Evaluate serum TTR levels in pts who transitioned from placebo+tafamidis to acoramidis in the open-label long term extension (OLE) study. Methods ATTRibute-CM study: Eligible pts with ATTR-CM were randomized in a 2:1 ratio to receive acoramidis or placebo for 30 months. Pts in both groups had the option of initiating open-label, commercially available tafamidis after 12 months in the study. Upon completion of Month 30, pts were invited to participate in the OLE study. In OLE, pts who had previously received acoramidis continued acoramidis, and those who had previously received placebo+tafamidis were switched to acoramidis-only treatment. All pts in the OLE study received acoramidis only. Change in serum TTR levels in ATTRibute-CM and OLE at data cutoff (Oct 9, 2023) are summarised using descriptive statistics. Results In the phase 3 study, efficacy analyses were performed in 611 pts, of which 61 of 409 (14.9%) and 46 of 202 (22.8%) received tafamidis in acoramidis and placebo groups, respectively. The median time until tafamidis initiation was 17.8 and 16.1 months, respectively; median exposure duration was 11.6 and 10.5 months, for acoramidis and placebo groups, respectively.[3] Change from baseline (CFB) in serum TTR levels remained unchanged at Month 30 in the placebo-only group (mean [SD] = –0.4 [4.92] mg/dL). Characteristics of pts analysed are described in Fig. 1. A total of 380/611 pts (62.2%) entered the OLE study (229 pts continued acoramidis only, and 23 switched from placebo+tafamidis to acoramidis). At the time of data cutoff, 214 pts who had received acoramidis only completed Month 6 in OLE versus 18 who switched from placebo+tafamidis to acoramidis. At Month 30 in ATTRibute-CM, CFB in serum TTR levels were higher for patients who received acoramidis only than those receiving placebo+tafamidis (Fig 2A). Serum TTR levels increased further in pts who switched from placebo+tafamidis to acoramidis in OLE (Fig. 2B). The OLE study is ongoing, and this analysis includes pts who completed the Month 6 visit at time of data-cut. Conclusion(s) CFB in serum TTR levels were higher in pts receiving acoramidis only than those receiving placebo+tafamidis at Month 30 in the double-blind study. A further significant increase in serum TTR levels was observed in those who received placebo+tafamidis and switched to acoramidis in OLE.

Abstract Magnesium (Mg) is an essential element involved in cellular metabolism. We demonstrated that in patients with diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (SCT), those with a serum Mg < 2.0 mg/dL at the time of transplant had worse outcomes. In this study, we aimed to learn the prognostic value of low serum Mg in patients with untreated DLBCL. We analyzed serum from 408 patients and tested 2 Mg cutpoints—low (<1.7 mg/dL) and low normal (<2.0 mg/dL), a range we found associated with lower survival in the SCT group. We found 3% of patients with low levels and 23% with low normal levels. Low normal serum Mg levels were associated with a higher stage at diagnosis, more extranodal involvement, higher international prognostic index score, lower overall survival (OS), and event-free survival. These data warrant testing Mg replacement to a target of >2.0 mg/dL to learn if survival can be improved.

Abstract Marginal zone lymphoma (MZL) includes extranodal MZL (EMZL), splenic MZL (SMZL), and nodal MZL (NMZL) subtypes. Histologic transformation (HT) to large B-cell lymphomas is well documented but with a large variability in published cumulative incidence rates. We report results from the Molecular Epidemiology Resource (MER) cohort on the cumulative incidence of HT (with death as competing risk) and the associated risk factors and outcomes. We also conducted a meta-analysis of available studies on the cumulative incidence of HT. From 2002 to 2015, 529 patients with MZL were enrolled in the MER study (69% EMZL, 16% SMZL, and 15% NMZL). The 10-year overall survival (OS) from diagnosis was 66%. HT occurred in 21 patients with a 5-year and 10-year cumulative incidence of 2.7% (95% confidence interval [CI], 0.02-0.05) and 3.6% (95% CI, 0.02-0.06), respectively. HT was associated with an increased risk for death (subdistribution hazard ratio [HR], 3.95; 95% CI, 2.06-7.55). Predictors of HT were ≥2 extranodal sites and mucosa-associated lymphoid tissue International Prognostic Index score ≥2. The OS was 79% at 5 years and 55% at 10 years after HT. In the meta-analysis of 12 studies (6161 patients), the 5- and 10-year cumulative incidence of HT across all subtypes were 5% (95% CI, 0.05-0.06) and 8% (95% CI, 0.07-0.09), respectively. These rates were lower in EMZL (3% and 5%) than in SMZL (7% and 13%) and NMZL (9% and 13%). Although HT is relatively uncommon in the first decade after MZL diagnosis, it is associated with an inferior outcome and needs new approaches for prevention and management.

Abstract Recent introduction of 2 different lymphoma classifications has raised concerns about consistency in diagnosis, management, and clinical trial enrollment. Data from a large cohort reflecting real-world clinical practice suggest that differences between the classifications will affect <1% of non-Hodgkin lymphomas.