Chan Y. Cheah

Cancer treatment reviews • January 15, 2025

Brian Grainger, Chan Cheah

Primary testicular lymphoma (PTL) is a rare extranodal lymphoma. The majority of cases are of diffuse large B cell lymphoma (DLBCL) histology (PT-DLBCL) with an activated B-cell-like (ABC) gene expression profile. These are characterised clinically by a high risk of contralateral testis and central nervous system (CNS) relapse, representing an ongoing area of unmet clinical need. Here, we review the epidemiology, clinical presentation and diagnostic evaluation of PT-DLBCL along with the advances in molecular biology that have occurred in the last decade, concerning the now-recognised molecular subtypes of DLBCL and their role of immune escape and sustained signalling in disease pathophysiology. We also appraise the retrospective and prospective clinical trials underpinning modern treatment recommendations, including the updated guidance on the role of radiotherapy and the latest evidence regarding strategies for preventing CNS relapse.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology • May 29, 2025

Toby Eyre, Chan Cheah, Clémentine Sarkozy, Anita Kumar, Steven Le Gouill

Mantle cell lymphoma (MCL) represents a relatively uncommon, heterogeneous lymphoma associated with limited overall survival. Targeting of the B-cell receptor pathway in relapsed disease with covalent Bruton tyrosine kinase (cBTK) inhibition has been demonstrated to be highly effective with cBTK inhibitor monotherapy, an established standard of care in relapsed MCL. This review summarizes the recent data strongly suggesting a role for the integration of covalent BTK inhibition in the first-line treatment setting, after the recent presentation and publication of multiple phase II and randomized phase II/III clinical trials demonstrating benefit for the addition of cBTK inhibitors first line. The authors discuss herein the strength and quality of the evidence for therapeutic strategies integrating cBTK inhibitors first line and proposal treatment algorithms on the basis of assumed future availability of this highly active small molecules first line in the near future.

Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology • May 01, 2025

Michael Wang, David Salek, David Belada, Yuqin Song, Wojciech Jurczak, Brad Kahl, Jonas Paludo, Michael Chu, Iryna Kryachok, Laura Fogliatto, Chan Cheah, Marta Morawska, Juan-manuel Sancho, Yufu Li, Caterina Patti, Cecily Forsyth, Jingyang Zhang, Robin Lesley, Safaa Ramadan, Simon Rule, Martin Dreyling

Background: The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival, but without improvement to overall survival likely due to toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. Methods: Patients aged ≥65 years with previously untreated mantle cell lymphoma received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus 6 cycles of bendamustine (90 mg/m2; days 1 and 2) and rituximab (375 mg/m2; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. Primary endpoint was progression-free survival per independent review committee; overall response rate and overall survival were secondary endpoints. Results: In total, 598 patients were randomized, with 299 in each arm. At a median follow-up of 44.9 months, median progression-free survival was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio, 0.73; 95% confidence interval, 0.57 to 0.94; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. Overall survival was not significantly different (hazard ratio, 0.86; 95% confidence interval, 0.65 to 1.13; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. Conclusions: Combination of acalabrutinib with bendamustine-rituximab significantly improved progression-free survival. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Expert Opinion On Investigational Drugs • May 01, 2025

Harry Hambleton, Chan Cheah

Follicular lymphoma (FL) is the most common indolent lymphoma. Patients with advanced-stage FL typically respond to therapy, then follow a relapsing/remitting course, with shorter progression-free survival with each subsequent line of therapy. Whilst existing CD19-directed therapies such as CAR T-cell therapy have shown promising efficacy in the management of relapsed/refractory FL, immune-mediated adverse events, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), are well described. AZD0486 is a fully human bispecific (CD19×CD3) T-cell engager (TCE) that induces T cell-mediated cytotoxicity but with low-affinity binding of CD3, resulting in a reduction in cytokine release. In this review, we describe the key preclinical data for AZD0486 and evaluate in detail the available clinical data from the ongoing phase 1 first-in-human study, including safety, efficacy, pharmacokinetics, and future development plans. Bispecific TCEs are among the most promising novel therapies in use for the management of relapsed/refractory B-cell lymphomas. AZD0486 results in high complete response rates with low incidence of high-grade immune-mediated toxicity compared to alternative TCE therapies. Importantly, it remains active in patients with lymphomas that have lost CD20 expression, an important mechanism of treatment failure following CD20 targeting TCEs.

British Journal Of Haematology • January 31, 2025

Catherine Tang, Catriona Downie, Mandeep Sagoo, Edward Pringle, Adam Suleman, Katharine Lewis, Lucy Zhang, Daire Quinn, L Poon, William Hann, Svetlana Cherepanoff, Luke Coyle, Shireen Kassam, Pamela Mckay, Chan Cheah, Anca Prica, Jeffery Smith, Nada Hama

Primary vitreoretinal lymphoma (PVRL) is a high-grade extranodal non-Hodgkin lymphoma, with limited prospective data to inform practice. High rates of central nervous system (CNS) relapse contribute to its poor prognosis. This international multicentre retrospective cohort study aimed to characterise real-world contemporary practice and outcomes in PVRL (2010-2022). Sixty patients were included from 11 centres across Australia, Singapore, Canada and the United Kingdom. Most patients had systemic therapy included in their initial management (63%) either alone or in combination with local therapies; 13% had upfront autologous stem cell transplantation (ASCT). The overall response rate was 78%. With a median follow-up of 68 months, the median progression-free survival (PFS) was 25 months, with a median overall survival (OS) of 73 months. Neither incorporation of systemic therapy into initial treatment nor upfront ASCT demonstrated a statistically significant impact on PFS or OS. The 5-year cumulative incidence of CNS relapse was 33%, with front-line systemic therapy being the only predictive factor for CNS relapse in a multivariate model, hazard ratio of 0.30 (95% CI 0.09-0.98, p = 0.05). Concerning heterogeneity in real-world approaches to diagnosis, staging and management approaches were identified. Further international collaborative efforts are required to address the unmet need in this rare entity.