Sehn, Laurie H.

Abstract A short diagnosis-to-treatment interval independently predicts inferior outcomes in follicular lymphoma. Using international discovery and validation cohorts, we demonstrate its prognostic value beyond established prognostic indices, with implications for risk stratification, clinical trial design, and interpretation.

Abstract Introduction Short diagnosis-to-treatment interval (DTI) is associated with aggressive disease biology and inferior outcomes in diffuse large B-cell lymphoma (DLBCL), and is recognized as a potential source of selection bias in clinical trials if not properly addressed. However, its prognostic significance in follicular lymphoma (FL) remains poorly characterized. We aimed to evaluate the prognostic significance of DTI in newly diagnosed FL patients who received frontline (1L) immunochemotherapy (IC), using a large international dataset and an independent external validation cohort. Methods For the discovery dataset, we evaluated patients diagnosed between 2002 and 2018 from ten observational cohorts as part of the FLIPI24 Consortium. External validation was conducted using data from patients enrolled in the Lymphoma Epidemiology of Outcomes (LEO) Cohort between 2010 and 2015. All patients had FL grade 1–3A and received 1L IC within 100 days of diagnosis. Patients with a concurrent DLBCL were excluded. Missing baseline laboratory values were addressed via multiple imputation. The primary endpoint was event-free survival at 24 months (EFS24); secondary endpoint was 5-year overall survival (OS), both calculated from treatment initiation. DTI was analyzed as continuous (via splines) and dichotomized variable (≤14 vs >14 days; as defined in DLBCL). Results In the discovery cohort (n=3,907), median age was 61 years (IQR 53–69), and 50% were male; 49% of patients were high-risk according to FLIPI, 26% according to PRIMA-PI, and 38% according to FLIPI24. Included patients received R-CHOP (54%), R-CVP (26%), or B-R (20%) as 1L treatment, followed by anti-CD20 maintenance in 60%. The median DTI was 30 days (IQR 17–48). Using the 14-day cut-off, 851 patients (22%) had short DTI. These patients had more adverse baseline characteristics, including B symptoms (42% vs 32%, P<0.01), ECOG performance status ≥2 (15% vs 8%, P<0.01), elevated LDH (51% vs 40%, P<0.01), hemoglobin <12 g/dL (30% vs 17%, P<0.01), and elevated β2-microglobulin (56% vs 44%, P<0.01). Prognostic indices (PIs) were also more frequently high-risk in the short-DTI group: FLIPI (56% vs 47%), PRIMA-PI (36% vs 24%), and FLIPI24 (51% vs 34%, all P<0.01). Spline modeling showed a decreasing EFS24 rate with increasing DTI, reaching a plateau at 30–40 days. In logistic regression model, each additional week of DTI improved EFS24 (OR 0.92, P<0.01). DTI attenuated but remained prognostic after adjusting for PIs (OR 0.93 for FLIPI, 0.95 for PRIMA-PI, 0.96 for FLIPI24, all P<0.01). When analyzed as a dichotomized variable, short DTI was associated with inferior EFS24: OR 1.74 adjusted for FLIPI, 1.63 for PRIMA-PI, and 1.53 for FLIPI24 (all P<0.01). The 2-year EFS of short vs long DTI groups was 71% vs 82% (HR 1.50, 95% CI 1.34–1.67, P<0.01), 5-year OS was 80% vs 86% (HR 1.38, 95% CI 1.21–1.56, P<0.01), and the 5-year cumulative risk of histologic transformation was 7.7% vs. 5.4% (P<0.01). In the validation cohort (n=516), median age was 61 years (IQR 52–69 years), 55% were male; 36% of patients were high-risk according to FLIPI; 29% according to PRIMA-PI, and 33% according to FLIPI24. Patients received B-R (59%) or R-CHOP (41%) as 1L treatment. The median DTI was 31 days (IQR 19–48), 84 patients (16%) had DTI ≤14 days. Similar patterns were observed; patients with short DTI had adverse baseline characteristics, PIs, and shorter 2-year EFS (72% vs 84%, HR 1.69, 95% CI 1.13–2.55, P=0.01). DTI remained associated with EFS24 when analyzed as a continuous variable (per week: OR 0.88 unadjusted, 0.90 with FLIPI, 0.89 with PRIMA-PI, and 0.89 with FLIPI24), and dichotomized (≤14 vs >14 days: OR 1.83 adjusted for FLIPI, 1.88 for PRIMA-PI, and 1.73 for FLIPI24). Conclusion Short DTI, defined as ≤14 days (observed in 22% of FL patients vs 46% in DLBCL), is a strong and independent predictor of inferior outcomes in newly diagnosed FL patients treated with IC. While DTI correlates with adverse baseline features and established PIs, it retains independent prognostic value. Although a 14-day threshold is reasonable for risk modeling, DTI contains greater informational value when modeled as a continuous variable. Among PIs, FLIPI24 most strongly attenuated the DTI effect, underscoring its superior discriminative power over FLIPI and PRIMA-PI. Clinical trials designs should mitigate any potential barriers to enrollment of FL patients requiring urgent therapy.

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 Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements (“double hit”; HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of and mechanisms driving IG vs non-IG MYC rearrangements have not been elucidated. Here, we used custom targeted capture and/or whole-genome sequencing to characterize oncogene rearrangements across 883 mature B-cell lymphomas including Burkitt lymphoma, follicular lymphoma, DLBCL, and HGBCL-DH-BCL2 tumors. We demonstrate that, although BCL2 rearrangement topology is consistent across entities, HGBCL-DH-BCL2 have distinct MYC rearrangement architecture relative to tumors with single MYC rearrangements or with both MYC and BCL6 rearrangements (HGBCL-DH-BCL6), including both a higher frequency of non-IG rearrangements and different architecture of MYC::IGH rearrangements. The distinct MYC rearrangement patterns in HGBCL-DH-BCL2 occur on the background of high levels of somatic hypermutation across MYC partner loci in HGBCL-DH-BCL2, creating more opportunity to form these rearrangements. Furthermore, because 1 IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B-cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.

PURPOSE CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication. PATIENTS AND METHODS Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti–CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts). RESULTS Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, –1.5 to 4.4; all-pts) and 1.4% (95% CI, –1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup. CONCLUSION In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.

AbstractDirect comparisons of the effectiveness of the numerous novel therapies in the diffuse large B‐cell lymphoma (DLBCL) treatment landscape in a range of head‐to‐head randomized phase 3 trials would be time‐consuming and costly. Comparative effectiveness studies using real‐world data (RWD) represent a complementary approach. Recently, several studies of relapsed/refractory (R/R) DLBCL have used RWD to create observational cohorts to compare patient outcomes with cohorts derived from single‐arm phase 2 trials. Using propensity score methods to balance clinically and prognostically relevant baseline covariates, closely matched patient‐level cohorts can be generated. By incorporating appropriate measures to assess covariate balance and address potential bias in comparative effectiveness study designs, robust comparative analyses can be performed. Results from such studies have been used to supplement regulatory approval of therapies assessed in single‐arm trials. While RWD studies have a greater susceptibility to bias compared to randomized controlled trials, well‐designed and appropriately analyzed studies can provide complementary real‐world evidence on treatment effectiveness.

Abstract With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.