Eliza A. Hawkes

A 35-year-old woman with stage III, diffuse large B-cell lymphoma (DLBCL) who relapsed within 12 months of frontline rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy, received second-line CD19-directed autologous chimeric antigen receptor T-cell (CAR-T) therapy with R-gemcitabine, dexamethasone, and cisplatin bridging. Day 30 post CAR-T positron emission tomography (PET) imaging demonstrated bulky stage IV disease progression. Secondary to tumor burden and prior therapy toxicity, the patient's Eastern Cooperative Oncology Group (ECOG) performance status was 2. She was considered for third-line CD3/CD20-directed bispecific antibody (BsAb) treatment.

Primary central nervous system lymphoma (PCNSL) is an aggressive lymphoma restricted to the CNS in which outcomes cannot be reliably predicted. The International PCNSL Collaborative Group developed standardized response assessment utilizing 2-dimensional (2D) Magnetic Resonance Imaging (MRI) tumor measurements. Considerable challenges of this approach exist due to many reasons. Recent glioblastoma and PCNSL data demonstrated that radiological assessment of baseline 3-dimensional volume (3DV) as well as 3DV reduction (3DVR) may be a sensitive prognostic parameter. Our multicentre retrospective study evaluated semiautomated 3DV in 74 PNCSL patients undergoing curative-intent chemoimmunotherapy. Baseline tumor 3DV was not associated with survival. Compared to 3DVR < 58% (ROC-determined threshold based on our cohort), both interim and End-of-Treatment (EOT) 3DVR ≥ 58% in responding patients were associated with statistically significant prolonged 2-year progression-free survival (PFS) (interim: 73% (95%CI 57-83) versus 22% (95%CI 3-51), P = 0.005; EOT: 75% (95%CI 59-85) versus 0%, P = 0.002) and 2-year OS (interim: 83% (95%CI 68-91) versus 38% (95%CI 9-67), P = 0.02; EOT: 86% (95%CI 70-93) versus 0%, P = 0.0002). However, no significant differences in PFS or OS were observed in patients achieving standard 2D complete response (CR) compared to partial response (PR). Although PCNSL tumor 3DV at baseline is not associated with survival outcomes, 3DVR of ≥58% in interim and EOT confers superior PFS and OS. Whereas, no difference in survival was observed using standard 2D CR versus PR response assessment at the same time-points. 3DV calculations may offer a sensitive method of response assessment for PCNSL. We are currently validating this in clinical trials.

Secondary central nervous system (CNS) lymphoma (SCNSL) in mantle cell lymphoma (MCL) is associated with dismal outcomes, and risk factors are not well documented. This population-based study reports the incidence of SCNSL, risk factors and survival. All patients diagnosed with MCL in Denmark in 2010-2022 without confirmed CNS involvement at diagnosis were included. Data were retrieved from the Danish National Lymphoma Registry and medical records. In total, 873 patients (median age 70 years) were included. The 10-year cumulative incidence of SCNSL was 3.8% (95% confidence interval [CI] 2.4-5.2). Risk factors for SCNSL were blastoid/pleomorphic MCL (hazard ratio [HR] 3.55, 95% CI 2.05-6.14), Ki67 ≥30% (HR 5.47, 95% CI 1.86-16.10) and elevated lactatedehydrogenase (HR 4.35, 95% CI 1.91-9.91). The 5-year cumulative incidence of SCNSL for patients with blastoid/pleomorphic MCL was 9.9% (95% CI 4.0-15.7). Patients with high CNS international prognostic index (CNS-IPI) had a high 1-year incidence of SCNSL of 5.8% (95% CI 1.6-10.0). Median progression-free survival and overall survival were 1.8 months (95% CI 1.3-4.7) and 2.4 months (95% CI 1.3-8.9). In conclusion, SCNSL of MCL is rare and associated with poor survival. Blastoid/pleomorphic subtype and high CNS-IPI identified patients at high risk of SCNSL for whom upfront screening for CNS involvement should be considered.

Tumour infiltrating lymphocyte (TIL) T-cell receptor (TCR) repertoire is prognostic in newly diagnosed diffuse large B-cell lymphoma (DLBCL), but evolution has not been evaluated at relapse. We examined the TCR repertoire in nine paired DLBCL samples from diagnosis and relapse. We noted considerable differences, with dominant clones at diagnosis replaced at relapse by new clones that were absent or minor initially. There was low linearity between diagnostic and relapsed samples (r-values 0.01-0.316), with shared clones averaging 8.3% (range 0%-37%). Clonal diversity was reduced in relapsed samples, suggesting an increasingly defunct intratumoural immune response. T-cell diversity is reduced in relapsed/refractory DLBCL, which may have implications for immunotherapy usage.

Novel CD3×CD20 bispecific antibody (BsAb) immunotherapies have entered the armamentarium for follicular lymphoma and diffuse large B-cell lymphoma based on accelerated approvals. The primary challenge in utilizing BsAbs lies in patient selection due to variable responses, unique toxicity, and health economics. To date, no validated biomarkers of therapy response exist, however data demonstrating potential clinical, imaging, and biological markers relating to BsAbs are growing. This review examines current prognostic and potentially predictive biomarkers and explores future directions for nuanced patient selection.

A Phase 2/3, Multicenter Randomized Study of Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP) with or Without Selinexor in Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma (RR DLBCL)

Frontline Treatment of Follicular Lymphoma With AtezolizUmab and Obinutuzumab With and Without RadiOtherapy

A Phase 2, Open-label Study of Zanubrutinib (BGB-3111) in Patients With Relapsed or Refractory Marginal Zone Lymphoma

Feasibility Study of Induction and Maintenance Avelumab Plus R-CHOP in Patients With Diffuse Large B Cell Lymphoma (DLBCL): The AvR-CHOP Study

Phase I Dose Escalation Study of Radiotherapy and Durvalumab in Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL) and Follicular Lymphoma (FL): The RaDD Study