Link, Brian K

Abstract Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Although patients with FL have high response rates to therapy, most develop increasingly resistant disease. In addition, transformation into an aggressive lymphoma is associated with unfavorable outcomes. Many novel agents are under investigation, and early clinical data are encouraging. Aligning treatment with the underlying tumor biology and sequencing of therapies remain key clinical challenges. At the Lymphoma Research Foundation’s biannual 2024 Follicular Lymphoma Scientific Workshop, experts convened to discuss the role of chemotherapy in the context of new therapies, the impact of early progression on treatment sequencing, novel end points in clinical trials, disease biology and the tumor microenvironment, and new treatments on the horizon. This report focuses on updates in FL biology, first-line treatment, the role of progression of disease in 24 months, clinical trial design, and redefining cure in FL.

PURPOSE Although most patients with follicular lymphoma (FL) can expect an indolent course, progressive lymphoma remains the primary cause of death during the first decade after diagnosis. Progression of disease within 24 months (POD24) of starting first-line (1L) immunochemotherapy defines a high-risk population with poor survival, but better risk stratification at diagnosis is needed. METHODS The FLIPI24 model was developed and internally validated to predict 24-month event rates using individual data from 4,485 patients treated with 1L immunochemotherapy from 10 observational cohorts of FL. Overall and cause-specific survival was further evaluated in FLIPI24 risk groups. External validation in the 1L immunochemotherapy setting was performed using the prospective observational Lymphoma Epidemiology of Outcomes (LEO) cohort (N = 565) and three randomized phase III trials (N = 3,192); extension to all patients with FL (any 1L therapy) was performed in the LEO cohort (N = 1,445) and its Molecular Epidemiology Resource subcohort (N = 1,074). RESULTS The FLIPI24 model uses age and four blood-based variables (hemoglobin, lactate dehydrogenase, beta-2 microglobulin, and WBC count). FLIPI24 showed consistent performance across validation and extension data sets, which was superior to existing prognostic tools. Across the four external immunochemotherapy validation data sets, patients with high-risk FLIPI24 (23%-32% of patients) had significantly higher 24-month event rates (22%-35%) and inferior 5-year overall survival (77%-83%) compared with patients with low-risk FLIPI24 (29%-31% of patients, 24-month event rates: 10%-12%; 5-year OS: 96%-97%). Results were consistent when evaluating lymphoma-related death and when extended to all patients with FL. CONCLUSION The FLIPI24 model robustly stratifies, at diagnosis, patients with FL at increased risk of lymphoma-related death versus patients with very low lymphoma-related mortality during the first decade after diagnosis. FLIPI24 can be used to enrich future clinical trial designs in newly diagnosed FL.

ABSTRACT Newly diagnosed patients with non‐Hodgkin lymphoma (NHL) often have a history of other diseases, and these comorbidities can impact patient treatment and management options, as well as overall survival (OS). We developed the Lymphoma Epidemiology of Outcomes (LEO) comorbidity index (LCI) as a sum of 10 comorbidities adapted from the Self‐Report‐Generated Charlson Comorbidity Index (SRG‐CCI) for use in the LEO cohort, a national prospective study of newly diagnosed NHL. Of the 5502 participants with self‐reported comorbidity data, 3107 (56.4%) were male and the mean age at diagnosis was 60.9 years (range, 18–99 years). The LCI ranged from 0 to 6, with 48.6% having 0, 30.2% having 1, 21.2% having 2 or more comorbidities. With a median follow‐up of 62.4 months among surviving participants, 2099 patients had an event and 1219 died. Continuous LCI similarly predicted both 1‐year mortality (c‐statistic = 0.654) and OS (c‐statistic = 0.655), while it showed a weaker but still statistically significant predictive ability for lymphoma‐specific (c‐statistics = 0.617) and event‐free (c‐statistic = 0.574) survival. Participants with 1 (HR = 1.21, 95% CI 1.05–1.39) and 2+ (HR = 1.80, 95% CI 1.56–2.08) comorbidities had inferior OS compared to those with no comorbidities after adjustment for age and sex (c‐statistic = 0.654), and performance strengthened after adjustment for the International Prognostic Index (c‐statistic = 0.672). LCI predicted OS most strongly in marginal zone (c‐statistics = 0.748) and weakest in T‐cell (c‐statistic = 0.579) lymphoma. The cumulative incidence of death due to lymphoma, lymphoma treatment, and other causes all increased with increasing comorbidities, with the greatest increase observed for death due to other causes. The LCI performs comparable to other published comorbidity indices, supporting its use in the LEO cohort to better model real‐world outcomes and more generally providing an approach to implementing comorbidity indices in cancer survivorship cohorts.

Abstract Although follicular lymphoma (FL) typically follows an indolent course, patients with FL who experience early events, such as transformation or progression, have increased risk of death related to lymphoma. The FL24Cx is an algorithm based on a 45-target gene expression profiling (GEP) assay, which was developed and trained using 265 formalin-fixed, paraffin-embedded tissue samples on a reliable platform to predict, at the time of diagnosis, whether a patient will experience an event within 24 months. The modeling also confirmed and relied upon previously reported synergy between immune response (IR) gene expression signatures IR1 and IR2. Once locked, the 5-factor logistic regression FL24Cx model was independently validated in a retrospectively assessed cohort of 232 patients from 2 immunochemotherapy-treated arms of SWOG Cancer Research Network S0016 phase 3 clinical trial, in which it assigned 169 patients to the low-risk group with 29 events before 24 months (17.2%) and 63 patients to the high-risk group with 24 events before 24 months (38.1%). The relative risk of an event within 24 months after registration among patients who were classified into the high-risk group relative to patients who were classified into the low-risk group was 2.2 (95% confidence interval, 1.41 to 3.51). An up-front GEP biomarker, such as the FL24Cx, rigorously validated in a clinical laboratory and with a clinically relevant turnaround time, could identify and steer enrollment of patients at high risk for early events in clinical trials, thus enabling timely interpretation of such trials and increasing the pace of innovation.

ABSTRACT Rituximab, gemcitabine, and oxaliplatin (R‐GemOx) is a commonly used chemoimmunotherapy regimen for relapsed or refractory (R/R) diffuse large B‐cell lymphoma (DLBCL), but there are limited real‐world data. In a multicenter retrospective study from a cohort of eight US academic centers (LEO CReWE), we evaluated 183 patients with R/R DLBCL and high‐grade B cell lymphoma treated with R‐GemOx, including subgroups treated without intent for consolidation with autologous stem cell transplant (ASCT) or chimeric antigen receptor (CAR) T cell therapy ( n = 100), those utilizing R‐GemOx as a bridge to ASCT or CAR T ( n = 83), and those aged 70 and older ( n = 71). Overall response rates (ORRs) for all patients treated with R‐GemOx were 45% with a complete response (CR) rate of 29%. The median event‐free survival (EFS) was 2.3 months, and the median overall survival (OS) was 13.5 months. Patients receiving R‐GemOx without intent for ASCT or CAR T had ORR and CR rates of 33% and 18%, respectively, with median EFS and OS of 2.0 and 9.5 months, respectively. Patients receiving R‐GemOx as a bridge to ASCT or CAR T had ORR and CR rates of 57% and 36%, respectively, with median EFS and OS of 3.5 and 17.4 months, respectively. Patients receiving R‐GemOx aged 70 and older had ORR and CR rates of 53% and 33%, respectively, with median EFS and OS of 2.2 and 13.9 months, respectively. These data provide a benchmark for R‐GemOx in the rapidly evolving landscape of R/R DLBCL therapies.

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.

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 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.