Identification of genetic subtypes in follicular lymphoma

Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and associated with a lower proliferative history than the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies

Lisocabtagene maraleucel in follicular lymphoma: The phase 2 TRANSCEND FL study

An unmet need exists for patients with relapsed/refractory (R/R) follicular lymphoma (FL) and high-risk disease features, such as progression of disease within 24 months (POD24) from first-line immunochemotherapy or disease refractory to both CD20-targeting agent and alkylator (double refractory), due to no established standard of care and poor outcomes. Chimeric antigen receptor (CAR) T cell therapy is an option in R/R FL after two or more lines of prior systemic therapy, but there is no consensus on its optimal timing in the disease course of FL, and there are no data in second-line (2L) treatment of patients with high-risk features. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product. The phase 2 TRANSCEND FL study evaluated liso-cel in patients with R/R FL, including 2L patients who all had POD24 from diagnosis after treatment with anti-CD20 antibody and alkylator ≤6 months of FL diagnosis and/or met modified Groupe d\u27Etude des Lymphomes Folliculaires criteria. Primary/key secondary endpoints were independent review committee-assessed overall response rate (ORR)/complete response (CR) rate. At data cutoff, 130 patients had received liso-cel (median follow-up, 18.9 months). Primary/key secondary endpoints were met. In third-line or later FL (n = 101), ORR was 97% (95% confidence interval (CI): 91.6‒99.4), and CR rate was 94% (95% CI: 87.5‒97.8). In 2L FL (n = 23), ORR was 96% (95% CI: 78.1‒99.9); all responders achieved CR. Cytokine release syndrome occurred in 58% of patients (grade ≥3, 1%); neurological events occurred in 15% of patients (grade ≥3, 2%). Liso-cel demonstrated efficacy and safety in patients with R/R FL, including high-risk 2L FL. ClinicalTrials.gov identifier: NCT04245839

Evaluating the impact of laboratory-based eligibility criteria by race/ethnicity in first-line clinical trials of DLBCL

Underrepresentation of racial and ethnic subgroups in cancer clinical trials remains a persistent challenge. Restrictive clinical trial eligibility criteria have been shown to exacerbate this problem. We previously identified that up to 24% of patients treated with standard immunochemotherapy would have been excluded from recent first-line trials in diffuse large B-cell lymphoma (DLBCL) based on 5 laboratory-based criteria. These ineligible patients had worse clinical outcomes and increased deaths related to lymphoma progression, suggesting the potential exclusion of patients who could have benefited most from the novel therapies being evaluated. Using data from the prospectively enrolled Lymphoma Epidemiology Outcomes cohort study, with demographics broadly similar to the US patients diagnosed with lymphoma, we evaluated the impact of laboratory eligibility criteria from recent first-line DLBCL trials across various racial and ethnic backgrounds. There were significant differences in the baseline laboratory values by race/ethnicity with Black/African American (AA) patients having the lowest mean hemoglobin and highest creatinine clearance. Based on recent clinical trial eligibility criteria, AA and Hispanic patients had higher rates of laboratory-based ineligibility than non-Hispanic White patients. The largest gap in the clinical outcomes between eligible and noneligible patients was noted within AA patients with an overall survival hazard ratio based on POLARIX clinical trial criteria of 4.09 (95% confidence interval, 1.83-9.14). A thoughtful approach to the utility of each criterion and cutoffs for eligibility needs to be evaluated in the context of its differential impact across various racial/ethnic groups

Matching-adjusted indirect comparison from the Lymphoma Epidemiology of Outcomes Consortium for Real World Evidence (LEO CReWE) study to a clinical trial of mosunetuzumab in relapsed or refractory follicular lymphoma

Mosunetuzumab is a novel bispecific antibody targeting epitopes on CD3 on T cells and CD20 on B cells with the goal of inducing T-cell mediated elimination of malignant B cells. A recent pivotal phase I/II clinical trial (GO29781) demonstrated that mosunetuzumab induced an overall response rate (ORR) of 80%, complete response (CR) rate of 60%, and a median progression-free survival (PFS) of 17.9 months in patients with relapsed/refractory (R/R) follicular lymphoma (FL) following at least two prior lines of systemic therapy, including alkylator and anti-CD20 antibody-based therapy. Historical data from cohorts receiving therapy for R/R FL can provide some context for interpretation of single-arm trials. We compared the results from the mosunetuzumab trial to outcomes from a cohort of patients with R/R FL from the LEO Consortium for Real World Evidence (LEO CReWE). We applied clinical trial eligibility criteria to the LEO CReWE cohort and utilized matching- adjusted indirect comparison weighting to balance the clinical characteristics of the LEO CReWE cohort with those from the mosunetuzumab trial. ORR (73%, 95% CI: 65-80%) and CR rates (53%, 95% CI: 45-61%) observed in the weighted LEO CReWE cohort were lower than those reported on the mosunetuzumab trial (ORR=80%, 95% CI: 70-88%; CR=60%, 95% CI: 49-70%, respectively). PFS at 12 months was similar in the weighted LEO CReWE (60%, 95% CI: 51-69%) and the mosunetuzumab (58%, 95% CI: 47-68%) trial. Sensitivity analyses examining the impact of matching variables, selection of line of therapy, and application of eligibility criteria provide context for best practices in this setting

Current directions in the treatment of classical Hodgkin lymphoma

Optimal management of patients who present with Hodgkin lymphoma continues to evolve. Most patients are cured with current treatment strategies, some but both short and long-term morbidity and mortality from treatment have particular relevance given the youth of the patient population. Combininations of targeted agents together with conventional chemotherapy have recently been investigated in phase 3 cliniial trials for advanced-stage Hodkgkin lymphoma, and have demonstrated improved efficacy compared with chemotherapy alone. These include both antibody-drug conjugates and PD-1 blockade. Treatment approaches have historically differed between pediatric and adult groups, but recent collaborations between adullt and pediatric groups via the NCTN mechanism have resulted in the successful completion of enrollment in an advanced-stage Hodgkin lymphoma and the opening of an early-stage trial that will enroll patients accross a broad age spectrum. Novel approachs incorporating targeted and immunomodulatory agents in the relapse setting are being actively investagated in the relapse setting as well

Tumor-immune signatures of treatment resistance to brentuximab vedotin with ipilimumab and/or nivolumab in Hodgkin lymphoma

UNLABELLED: To investigate the cellular and molecular mechanisms associated with targeting CD30-expressing Hodgkin lymphoma (HL) and immune checkpoint modulation induced by combination therapies of CTLA4 and PD1, we leveraged Phase 1/2 multicenter open-label trial NCT01896999 that enrolled patients with refractory or relapsed HL (R/R HL). Using peripheral blood, we assessed soluble proteins, cell composition, T-cell clonality, and tumor antigen-specific antibodies in 54 patients enrolled in the phase 1 component of the trial. NCT01896999 reported high (\u3e75%) overall objective response rates with brentuximab vedotin (BV) in combination with ipilimumab (I) and/or nivolumab (N) in patients with R/R HL. We observed a durable increase in soluble PD1 and plasmacytoid dendritic cells as well as decreases in plasma CCL17, ANGPT2, MMP12, IL13, and CXCL13 in N-containing regimens (BV + N and BV + I + N) compared with BV + I (P \u3c 0.05). Nonresponders and patients with short progression-free survival showed elevated CXCL9, CXCL13, CD5, CCL17, adenosine-deaminase, and MUC16 at baseline or after one treatment cycle and a higher prevalence of NY-ESO-1-specific autoantibodies (P \u3c 0.05). The results suggest a circulating tumor-immune-derived signature of BV ± I ± N treatment resistance that may be useful for patient stratification in combination checkpoint therapy. SIGNIFICANCE: Identification of multi-omic immune markers from peripheral blood may help elucidate resistance mechanisms to checkpoint inhibitor and antibody-drug conjugate combinations with potential implications for treatment decisions in relapsed HL