Laurie Helen Sehn

Summary: Comprehensive genome and transcriptome profiling can inform the diagnosis, prognosis and management of relapsed/refractory (R/R) solid malignancies, yet its integration into clinical care has lagged despite strong biological rationale. We evaluated the clinical utility of whole genome and transcriptome analysis (WGTA) in 65 patients (37 paediatric, 14 adolescents and young adults, 14 adults) with R/R non‐Hodgkin lymphomas enrolled in Canadian precision oncology initiatives (Personalized Oncogenomics, Precision Oncology for Young People, Personalized Targeted Therapy in Refractory or Relapsed Cancer in Childhood, SickKids' Cancer Sequencing). WGTA provided clinically potentially useful findings in 89% of patients including therapy selection, diagnostic clarification, prediction of resistance, minimal residual disease marker identification and discovery of germline cancer predisposition. Results altered management in 15% of patients. Barriers to implementation included clinical deterioration, availability of standard therapies reducing the need for sequence‐informed therapies and limited access to targeted agents. Transcriptome‐based clustering delineated five biologically distinct subgroups independent of age or histological subtype with convergent oncogenic pathways. Mutational signature analysis identified hypermutation patterns consistent with genomic damage associated with prior cytotoxic therapies. While our findings support the integration of WGTA into the care of patients with R/R lymphomas and identify opportunities for sequence‐guided treatment, drug access, systematic barriers and delayed timing of testing currently limit clinical uptake and the potential of precision oncology in lymphoid malignancies.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and remains curable for many patients with frontline immunochemotherapy; however, optimal treatment continues to evolve. The Canadian Hematology Consensus Group convened a national panel of lymphoma experts to develop evidence-informed recommendations for the first-line management of adults with DLBCL in Canada. Recommendations were developed using a modified Delphi process and address frontline regimen selection, treatment intensity, central nervous system (CNS) risk assessment and prophylaxis, interim response assessment, and end of treatment management. The panel recommends Pola-R-CHP for patients with international prognostic index 2–5 and activated B-cell subtype by gene expression profiling (or if unavailable, non-germinal centre B-cell subtype by immunohistochemistry). All patients should be assessed for fitness to receive full-dose therapy, with dose attenuation considered when clinically appropriate. Routine high-dose methotrexate prophylaxis is not recommended, and CNS screening should be individualized. Interim imaging may be used to confirm response, but treatment escalation should not be based on PET positivity alone. Patients achieving complete metabolic response at end of treatment require no further therapy, and routine surveillance imaging is not recommended. These recommendations support consistent, evidence-informed, and equitable care for patients with newly diagnosed DLBCL across Canada.

Relapsed and/or refractory follicular lymphoma (R/R FL) remains a therapeutic challenge due to its chronic relapsing course and increasingly complex treatment landscape. Novel therapies, including immunomodulatory combinations, bispecific antibodies (BsAbs), Bruton tyrosine kinase inhibitors, and chimeric antigen receptor (CAR) T-cell therapies, have expanded treatment options and increased the complexity of treatment selection and sequencing. The Canadian Hematology Consensus Group (CHCG) convened a national panel of lymphoma experts to develop evidence-informed consensus recommendations for the management of adults with R/R FL in the Canadian context. Clinical questions informed a structured literature review of studies published through February 2026, including randomized trials, phase II studies, observational data, conference proceedings, and relevant guidelines. Recommendations were developed using a modified Delphi consensus process and graded using a framework adapted from the British Committee for Standards in Haematology. Key recommendations include repeat biopsy to exclude histologic transformation at relapse, individualized treatment selection based on timing of relapse and patient-specific factors, preferential use of lenalidomide-rituximab (LenR)-based triplet combinations in most second-line settings, and incorporation of BsAb and CAR T-cell therapy in third-line and later disease. These recommendations aim to provide practical guidance for Canadian clinicians managing patients with R/R FL.

Diffuse large B-cell lymphoma (DLBCL) is a biologically heterogeneous disease. Two genomic classification systems, LymphGen and DLBclass, are capable of reproducibly classifying single tumors into subtypes with prognostic relevance in the context of standard-of-care R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemoimmunotherapy. Preliminary data from subgroup analyses of clinical trials suggest that the distinct biological features are targetable with drugs that exploit subtype-specific vulnerabilities, and large clinical trials are being designed to test this hypothesis. Although whole-exome sequencing (WES) remains the gold standard for each of these classification systems, smaller targeted sequencing panels reduce costs associated with sequencing, data storage, and processing. Here, we describe the design and validation of a targeted sequencing panel (LySeqST) that captures the genomic features required specifically for LymphGen classification. We perform in silico theoretical and real-world validation vs WES data and demonstrate that LySeqST can be used to accurately classify DLBCL tumors using both LymphGen and DLBclass. In an unselected population-based cohort, we determine the real-world proportions and validate the prognostic relevance of LymphGen subtypes, confirming that only tumors expressing the dark zone gene expression signature are consistently associated with inferior outcomes. Our results support the use of LySeqST for accurate genomic classification of DLBCL.

Patients with diffuse large B-cell lymphoma (DLBCL) with late relapse (>2 years from diagnosis) may be treated with a second course of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–like therapy particularly if comorbidities preclude more intensive options. Patients with de novo DLBCL initially treated with an R-CHOP–like regimen who later developed late relapse and were re-treated with curative-intent R-CHOP–like therapy were identified using the BC Cancer databases. Sixty-five patients were identified; at relapse, the median age was 77 years (range, 52-89), 81% had stage III to IV DLBCL, 52% had an Eastern Cooperative Oncology Group performance status of 2 to 4, and 78% had an International Prognostic Index score of 3 to 5. The median time from original diagnosis was 7.4 years (range, 2.5-15.9). Median number of cycles of R-CHOP–like therapy received at relapse was 5 (range, 1-6). Overall response rate was 72%, and 57% complete response. With a median follow-up of 31 months, 2-year time to progression (TTP) was 54%, 2-year progression-free survival was 46%, 2-year disease-specific survival was 64%, and 2-year overall survival was 54%. Patients relapsing >5 years from diagnosis had better TTP, with a 2-year TTP of 66% compared with 9% for patients relapsing between 2 and 5 years (hazard ratio, 0.30; 95% confidence interval, 0.14-0.64; P = .001). Many patients with late-relapsing DLBCL may be effectively treated with further R-CHOP–like therapy, avoiding more intensive and costly secondary therapies.

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.

In the POLARIX study (ClinicalTrials.gov identifier: NCT03274492 ), polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) showed a significant progression-free survival (PFS) benefit versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated intermediate- or high-risk diffuse large B-cell lymphoma (DLBCL; median follow-up: 28 months). In this 5-year update, sustained PFS benefits favoring Pola-R-CHP were observed. In the global intention-to-treat population (N = 879; median follow-up: 64.1 months), Pola-R-CHP demonstrated a significant PFS benefit over R-CHOP (hazard ratio [HR], 0.77 [95% CI, 0.62 to 0.97]), with 5-year PFS rates of 64.9% (95% CI, 59.8 to 70.0) and 59.1% (95% CI, 53.9 to 64.3), respectively. Although not statistically significant, overall survival analysis showed a HR of 0.85 (95% CI, 0.63 to 1.15) at the 5-year data cut compared with 0.94 (95% CI, 0.67 to 1.33) at the 2-year data cut. In the expanded population, 46 and 62 patients had lymphoma-related deaths in the Pola-R-CHP and R-CHOP arms, respectively. Exploratory analyses showed favorable 5-year survival rates with Pola-R-CHP in high-risk subgroups, including activated B-cell DLBCL and International Prognostic Index score 3-5. Long-term tolerability was similar between treatment arms. Findings confirm Pola-R-CHP represents a standard of care for frontline treatment of DLBCL.

In the pivotal ZUMA-7 trial, second-line (2L) treatment with axicabtagene ciloleucel (axi-cel) had superior clinical outcomes compared to standard of care (SOC; salvage chemoimmunotherapy followed by high-dose therapy and autologous stem cell transplant in responders) in patients with large B-cell lymphoma (LBCL) who were refractory or relapsed (r/r) within 12 months of completion of frontline therapy. The aim of this analysis was to evaluate the cost-effectiveness of axi-cel compared to SOC for 2L LBCL in Canada. A 3-health state partitioned-survival model was used to estimate the cost-effectiveness of axi-cel vs. SOC from a Canadian healthcare system perspective. Clinical outcomes were informed by ZUMA-7. The model calculated expected quality-adjusted life years (QALYs), total costs, and the incremental cost-effectiveness ratio (ICER). Over a lifetime horizon, the model estimated a total of 9.48 and 7.25 QALYs, and total costs of $569,168 and $337,906 for axi-cel and SOC, respectively, resulting in an ICER of $103,810/QALY. When adjusting for the substantial proportion of patients in the SOC arm who received cellular therapy as subsequent treatment, the ICER was reduced to $78,555/QALY. Treatment with axi-cel in 2L is a cost-effective option that addresses an important unmet clinical need for Canadian patients with r/r LBCL.

CAR-T cell therapy has significantly improved outcomes for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but challenges such as limited resources, manufacturing timelines, and notable toxicities persist. Bispecific antibodies (BsAbs), including glofitamab and epcoritamab, have demonstrated promising efficacy and represent a new treatment option in patients who are unsuitable for or have relapsed following CAR-T therapy. Bispecific antibodies have a manageable safety profile and are generally more widely accessible than CAR-T cell therapy. Case discussions in this paper illustrate the potential real-world application of BsAbs, highlighting their role in treating patients who have relapsed after or are unable to undergo CAR-T cell therapy. Overall, glofitamab and epcoritamab represent valuable treatment options in the evolving landscape of R/R DLBCL.