Faculty Bibliography

The phase III AUGMENT trial (ClinicalTrials.gov identifier: NCT01938001) demonstrated improved efficacy for lenalidomide plus rituximab (R²) versus rituximab with placebo (R-placebo) in patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Here, we present the long-term follow-up results and prespecified subgroup analyses of patients with follicular lymphoma (FL), including those 70 years and older. Patients with R/R grade 1 to 3a iNHL were randomly assigned 1:1 to receive R² or R-placebo. In this long-term follow-up report, progression-free survival (PFS) was assessed per the investigator. Secondary end points included overall survival (OS) and safety. Of the 358 randomly assigned patients (intent-to-treat [ITT] population), 295 had FL (≥70 years, n = 66). At long-term follow-up (median, 65.9 months), in the ITT iNHL population, PFS (hazard ratio [HR], 0.50 [95% CI, 0.38 to 0.66]) and OS (HR, 0.59 [95% CI, 0.37 to 0.95]) were improved with R² versus R-placebo. Safety findings were consistent with the primary analysis. Improved long-term efficacy with R² versus R-placebo and manageable safety with R² were observed in patients with FL, including those 70 years and older. With a follow-up of >5 years, data from the AUGMENT trial continue to support the use of R² as a standard of care for patients with R/R iNHL.

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.

This phase 2 study evaluated the efficacy and safety of combining acalabrutinib (A) and lenalidomide (L) with either rituximab (ALR) or obinutuzumab (ALO), with longitudinal minimal residual disease (MRD) monitoring in frontline MCL treatment (ClinicalTrials.gov - NCT03863184). The primary objective was molecular CR after 12 cycles of induction, defined by Lugano criteria and undetectable MRD <10-6 (uMRD6) by clonoSEQ. Secondary objectives included safety, responses and survival. Exploratory objectives included tumor mutation profiles and cell-free DNA (cfDNA) by CAPP-Seq. Patients in uMRD6 molecular CR were eligible for discontinuation of A+L after 24 cycles; all patients received a minimum of 36 cycles of anti-CD20 antibody treatment. In the ALR cohort, grade 3-4 hematologic toxicities included neutropenia (38%), thrombocytopenia (4%) and anemia (4%). Non-hematologic toxicities included rash (42%), fatigue (4%), nausea (4%), and vomiting (4%). The ORR was 100%, CR 83% and molecular CR 67% after 12 cycles of induction, with best molecular CR at 83%. At a median follow-up of 53 months (range 46-60), the 4-yr OS and PFS for ALR were 91% and 76%, respectively. TP53 mutations were adversely associated with PFS (p=0.026). For ALO, ORR, CR and molecular CR were 90% following induction, and 2-yr OS and PFS were both at 100%. Longitudinal cfDNA analysis in ALR revealed clonal evolution during response and progression. This safe and active regimen is feasible as a time-limited initial therapy for MCL patients and warrants further evaluation in response-adapted strategy.

Few prospective benchmark studies exist to characterize the evolving contemporary real-world practice for PTCL. We report the patterns of first-line care and outcomes for 720 patients with systemic PTCL enrolled in two related prospective cohort studies, LEO from 2015-2020 (ClinicalTrials.gov NCT02736357) and MER from 2002-2015, both followed through 2024. The primary endpoints were EFS and OS using Kaplan-Meier estimator and Cox regression model. Secondary endpoints included correlations of clinical and treatment factors with survival. The most common induction regimens were CHOP-based (70%), given as CHOP (36%), CHOP plus etoposide (23%), or CHOP-like plus novel agents (11.5%, including 5% BV-CHP). Consolidative autologous stem cell transplant was performed in 102 patients (14%). Within nodal PTCL, EFS and OS were adversely associated with IPI 2-5 (HR=2.00, 95%CI: 1.59-2.52 for EFS; HR=2.44, 95%CI: 1.86-3.19 for OS), PIT 1-4 (HR=3.02, 95%CI 2.07-4.39 for EFS; HR=5.10, 95%CI 3.01-8.63 for OS), and non-ALCL subtypes (HR=2.97, 95%CI: 2.26-3.91 for EFS; HR=3.71, 95%CI: 2.65-5.20 for OS). Within LEO, which captured increasing first-line etoposide and BV, adding etoposide to CHOP was associated with better OS in ALK-negative ALCL (HR=0.14, 95%CI: 0.03-0.69, p=0.015). BV-CHP showed a trend toward OS improvement in ALCL (HR=0.15, 95%CI 0.02-1.19, p=0.073). Patients failing EFS6 and EFS24 had 5-year subsequent OS of 12% (95% CI: 7.8%, 19%) and 17% (95% CI: 13%, 22%), respectively. The inferior outcomes in non-ALCL subtypes and patients failing EFS6 and EFS24 highlight unmet needs with CHOP-based induction, where clinical trials with targeted therapy should be prioritized.

Progress in the therapy of follicular lymphoma (FL), the most common indolent lymphoma subtype, has been achieved in recent years with significant improvement in median overall survival. Most patients diagnosed with FL will now die from other causes. Multiple novel immunotherapy and other targeted therapies are now approved for relapsed and refractory disease. However, early progression and transformation to aggressive lymphoma remain key issues requiring further innovation. We expect that bispecific antibodies will likely move to earlier use and in novel combinations. Future generations of these and chimeric antigen receptor T-cell therapy will be developed in an effort to minimize toxicity and improve efficacy. New technologies, such as circulating tumor DNA assays, may enable more rational selection and guidance of therapy duration or changes in treatment, as well as possibly substituting for follow-up imaging while monitoring patients. We also look forward to more extensive use of quality-of-life tools to select treatment for patients who have a favorable long-term outlook with multiple options. Finally, patients and clinicians now envision a day when FL is no longer referred to as "incurable." Having a definition and possibility of a "cure" and being able to optimize such a mindset in the approach of FL would represent a major advance in our future management strategy.

To improve outcomes in relapsed or refractory activated B-cell type Diffuse Large B-cell Lymphoma (ABC-DLBCL), we launched a randomized phase 3 trial evaluating 2-year progression free survival (2yPFS) with the addition of ibrutinib to autologous transplant. Patients received ibrutinib 560 mg or placebo with conditioning and for 12 additional cycles. Accrual was adversely affected by implementation of the ABC classifier in this setting and the changing treatment landscape of DLBCL. In all, 39 patients on ibrutinib and 38 on placebo were evaluable. 2yPFS was 57.6% on ibrutinib versus 40.8% on placebo (p = 0.09). We observed a higher incidence of grade ≥3 sepsis (10% vs 5%) and mucositis (13% vs. 3%) on ibrutinib but similar rates of atrial fibrillation. There were 4 fatalad verse events in the ibrutinib arm due to infection. Ibrutinib added to transplant may improve 2yPFS in relapsed/refractory ABC-DLBCL but future clinical trials should incorporate more efficient patient selection.

Older patients with classic Hodgkin lymphoma (cHL) have inferior survival compared with younger patients. We report a subset analysis of older patients (60 years and older) enrolled in the phase three S1826 trial conducted by SWOG that randomly assigned patients with newly diagnosed advanced-stage (III-IV) cHL to six cycles of nivolumab (N)-AVD or brentuximab vedotin (BV)-AVD. Of 103 enrolled patients 60 years and older, 99 were eligible. At a median follow-up of 2.1 years, the 2-year progression-free survival was 89% after N-AVD (n = 50) and 64% after BV-AVD (n = 49, HR 0.24, 95%CI 0.09-0.63, 1-sided stratified log-rank P = .001). The 2-year OS was 96% with N-AVD versus 85% with BV-AVD (HR 0.16, 95%CI 0.03-0.75 stratified 1-sided log-rank P = .005). Six cycles were delivered without dose reduction in 69% on N-AVD and 26% on BV-AVD; 55% discontinued BV, and 14% discontinued nivolumab. The nonrelapse mortality was 16% with BV-AVD and 6% with N-AVD. Despite more neutropenia with N-AVD, febrile neutropenia, sepsis, and infections were higher with BV-AVD, as was peripheral neuropathy. Patient-reported outcomes of key adverse events confirmed the improved toxicity profile of N-AVD over BV-AVD. N-AVD was better tolerated and more effective than BV-AVD and is therefore a new standard of care for older patients with advanced-stage cHL fit for anthracycline-based combination therapy.

Peripheral T-cell lymphoma (PTCL) is characterized by clinicopathologic heterogeneity with a frequently relapsing/refractory (R/R) course. The optimal sequencing and efficacy of novel agents and SCT in second-line and beyond remains yet to be determined. The objective of this dual-institution retrospective study is to assess outcomes in R/R nodal PTCL with respect to SCT and novel agents. A total of 148 patients were reviewed for baseline characteristics and treatment parameters. Endpoints were subsequent EFS (sEFS) and subsequent overall survival (sOS). The median sEFS and sOS for the entire cohort was 5.3 m (95% CI: 4.1 - 7.1) and 32.4 m (95% CI: 17.7 - 71.0), respectively. The median sEFS favored patients who received salvage SCT following either chemotherapy or novel agents (p = 0.005). The median sOS showed similar trend. Altogether, these data suggest that incorporation of novel agents in patients with and without SCT in second-line and beyond may improve outcomes compared to historical cohorts.

Despite high response rates, anti-programmed death 1 (anti-PD-1) monotherapy eventually fails in most patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) and is ineffective in most other B-cell malignancies. The lymphocyte activation gene 3 (LAG-3) cell-surface receptor represents another immune checkpoint that can be targeted to induce remissions in these diseases; dual inhibition of PD-1 and LAG-3 is approved in advanced melanoma. We performed a multicenter phase 1/2a open-label study of the anti-LAG-3 antibody relatlimab (RELATIVITY-022) administered as monotherapy or in combination with nivolumab in patients with R/R B-cell malignancies. We treated 106 patients and no dose-limiting toxicities were observed during escalation. The recommended phase 2 dose was relatlimab 240 mg as monotherapy or nivolumab 240 mg plus relatlimab 160 mg, administered every 2 weeks. No unexpected safety signals were observed compared with anti-PD-1 monotherapy. In the HL expansion cohorts, objective response rate (ORR) was 62% and complete response rate (CRR) was 19% in anti-PD-1/anti-programmed death ligand 1 (anti-PD-[L]1)-naive patients (n = 21), with a median progression-free survival (PFS) of 19 months; ORR was 15% and CRR 0%, with median PFS of 6 months in anti-PD-(L)1-progressed patients (n = 20). In diffuse large B-cell lymphoma, ORR was 7% with no CRs (n = 15), and median PFS was 2 months. Nivolumab plus relatlimab appeared to be safe and tolerable. Responses in patients with anti-PD-(L)1-naive HL was encouraging, although the contribution of relatlimab to overall efficacy of the combination needs to be further evaluated. This trial was registered at www.ClinicalTrials.gov as #NCT02061761.