Christopher Paul Fox

Purpose: Subsequent primary malignancies (SPMs) are the leading cause of long-term treatment-related mortality in Hodgkin lymphoma (HL). Although treatments have evolved substantially over recent decades, few studies have demonstrated reductions in SPM risks following modern treatments, nor how such changes should inform survivorship care and screening. We analyzed SPM risks in a large female cohort of childhood and adult patients with HL treated over a 60-year period. Materials and Methods: This population-based cohort study included 7,428 women diagnosed with HL before age 36 years in England and Wales from 1954 to 2010, with follow-up through 2018. SPMs were ascertained via national cancer registry linkages. Standardized incidence ratios (SIRs), absolute excess risks, and multivariable models were used to assess temporal trends and associations with treatment. Results: During a median follow-up of 20.2 years, 1,200 women developed 1,467 invasive cancers (SIR, 3.3 [95% CI, 3.1 to 3.5]), most commonly breast, lung, and thyroid cancers. Solid tumor risks were the highest following radiotherapy, with a strong dose-dependent response. Alkylator use with radiotherapy was associated with reduced risks of breast cancer but increased risks of GI cancers. Solid cancer risks decreased by 25% between treatment periods 1954-1989 and 2000-2010. The decrease was attenuated and nonsignificant after adjustment for radiotherapy but not affected by adjustment for chemotherapy. No decline was observed for hematologic malignancies. Cumulative incidence of SPMs reached 36% at 50 years. Conclusion: Female patients treated in more recent eras have a substantially lower long-term risk of solid SPMs largely attributable to the reduced use, dose, and improvement in radiotherapy. Nevertheless, persistently elevated risks remained beyond 50 years of follow-up, particularly for lung and breast cancer, underscoring the need for lifelong surveillance and targeted screening of survivors.

Summary: Peripheral T‐cell lymphomas (PTCL) are rare chemoresistant malignancies with poor outcomes, necessitating novel therapies. The programmed death‐1 (PD‐1)/programmed death ligand 1 (PD‐L1) axis is frequently overexpressed in PTCL and represents a potential therapeutic target; however, PD‐L1 inhibition has not been explored. We conducted a phase IIa trial evaluating avelumab, an anti‐PD‐L1 antibody, in relapsed/refractory PTCL. The primary end‐point was overall response. Translational substudies included PD‐L1 expression, circulating tumour DNA and baseline mass cytometry in a subset of patients. Of 35 recruited patients, 32 initiated treatment, although 13 discontinued early due to progression before the 3‐month evaluation. Intention‐to‐treat analysis showed an overall response rate of 14.3%, median progression‐free survival of 2.8 months (95% confidence interval [CI]; 1.8–3.4) and median overall survival of 10.3 months (95% CI; 6.0–12.3). In the five responding patients, median duration of response was not reached (12‐month duration of response [DoR] rate 60% [95% CI; 13–88]). In a subset of patients, mass cytometry revealed marked perturbations in circulating T‐cell subsets. Pathogenic variants detected in cell‐free deoxyribonucleic acid (DNA) underscore the utility of liquid biopsy in PTCL, and longitudinal analysis revealed clonal dynamics. While avelumab demonstrated durable responses in a minority, most patients progressed early. Further studies are needed to define mechanisms of response and develop predictive biomarkers to guide strategies.

Summary: Primary mediastinal B‐cell lymphoma (PMBCL) is a distinct clinicopathological entity within the spectrum of aggressive B‐cell lymphomas, characterised by unique clinical, immunophenotypic and molecular features. Since publication of the 2019 British Society for Haematology (BSH) Good Practice Paper, there have been important advances in imaging, radiotherapy approaches and systemic therapies, including chimeric antigen receptor (CAR) T‐cell therapy and immune checkpoint inhibition. Key updates include the use of PET‐adapted approaches to guide radiotherapy decisions following first‐line chemoimmunotherapy, with omission of consolidative radiotherapy in patients achieving complete metabolic response. The guideline emphasises the importance of dose‐intensive chemoimmunotherapy regimens and provides a framework for the clinical management of patients with Deauville stage 4 (DS4) and DS5 response status on PET‐CT imaging following chemoimmunotherapy.

Background: The optimal monitoring strategy for adults with inflammatory conditions established on immune-suppressing treatment is unknown. Objectives: To ascertain the optimum strategy of monitoring blood tests for patients established on immune-suppressing drugs. The objectives were to: investigate the association between different strategies of monitoring and detection of pre-specified haematological, hepatic or renal side effects identify prognostic factors associated with pre-specified haematological, hepatic or renal side effects develop prediction models for pre-specified haematological, hepatic or renal side effects evaluate cost-effectiveness of testing strategies, and explore patients’ and clinicians’ experiences of current testing strategies, and acceptability of recommended strategies. Design: The study undertook systematic review, prognostic modelling, health economic modelling of alternate monitoring intervals, and qualitative study. Setting: Primary and secondary care. Participants: Data from the UK’s Clinical Practice Research Datalink and British Association of Dermatologists Biologics Register were used for prediction modelling. Patients with inflammatory conditions treated with immune-suppressing drugs and health professionals were interviewed. Results: There were differences in testing strategies used, outcome definitions and follow-up precluding evidence synthesis. However, clinically significant pre-specified side effects were found to be uncommon or very uncommon during long-term treatment. There was high-quality evidence for elevated liver enzymes and folate non-supplementation being prognostic for methotrexate hepatotoxicity, mercaptopurine being prognostic for thiopurine hepatotoxicity and myelotoxicity; poor thiopurine metabolizer being prognostic for cytopenia; and elevated liver enzymes being prognostic for hepatotoxicity due to anti-tumour necrosis factor-alpha. Five prediction models were developed and validated. They had excellent performance characteristics. The calibration slope (95% confidence interval) in validation cohort was 0.94 (0.85 to 1.02) for methotrexate, 1.10 (0.84 to 1.36) for thiopurines, 0.91 (0.74 to 1.07) for leflunomide, 1.19 (0.96 to 1.43) for sulfasalazine, and 0.90 (0.61 to 1.19) for 5-aminosalicylates. Prediction modelling could not be undertaken for anti-tumour necrosis factor-alpha and mycophenolate due to few outcomes. Health economic modelling found it was cost-effective to increase the interval between monitoring blood tests except in very high-risk scenarios for some drugs (e.g. biennial testing in leflunomide). Eighteen patients from a range of risk profiles, and 13 health professionals were interviewed remotely. They found it acceptable to increase the interval between monitoring blood tests from 3-monthly to 6-monthly or annually depending on their risk profiles. Limitations: It was not possible to synthesise the association between different strategies of testing and detection of pre-specified side effects. A meta-analysis of prognostic factors was not possible. Conclusions: Clinically significant myelotoxicity, hepatotoxicity and nephrotoxicity are uncommon during long-term immune-suppressing drug treatment and were predicted using readily available information. Extending the intervals between monitoring blood tests was more cost-effective than the current practice. It was acceptable to patients and health professionals to increase the interval between monitoring blood tests. Future work: Test clinical effectiveness, undertake knowledge mobilisation, validate in non-UK populations. Research on other biologics. Study registration: The study is registered as PROSPERO CRD42020208042, CRD42020208042 and the interview studies were registered on ClinicalTrials.gov NCT05458531. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR130580) and is published in full in Health Technology Assessment ; Vol. 30, No. 64. See the NIHR Funding and Awards website for further award information.

PURPOSE: Peripheral T-cell lymphomas (PTCLs) are rare, heterogeneous, aggressive lymphomas. Five-year overall survival (OS) remains approximately 30%-40%, and most patients will develop relapsed or refractory (R/R) disease. Duvelisib is an oral dual inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ and PI3K-γ isoforms. Here, we report on the final analysis of the phase II PRIMO trial (ClinicalTrials.gov identifier: NCT03372057 ; Secura Bio, Inc) evaluating duvelisib monotherapy in R/R PTCL. METHODS: PRIMO was conducted in two phases (dose optimization and dose expansion [PRIMO-EP]) at 45 centers globally. Eligible patients were age 18 years and older, had histologically confirmed diagnosis of PTCL, and had received ≥2 cycles of one standard regimen for PTCL. Based on dose optimization results, the selected regimen for PRIMO-EP was 75 mg twice a day for two cycles (to maximize disease control) followed by 25 mg twice a day (to reduce late toxicities), continued until progressive disease or unacceptable toxicity. RESULTS: PRIMO-EP (N = 123) outcomes included independent review committee–assessed objective response rate (ORR): 48.0%, complete response rate (CRR): 33.3%, median progression-free survival (mPFS): 3.4 months, median OS (mOS): 12.4 months, and median duration of response (mDOR): 7.9 months. In the angioimmunoblastic T-cell lymphoma (AITL) subgroup, outcomes were ORR: 62.2%, CRR: 51.4%, mPFS: 8.3 months, mOS: 18.1 months, and mDOR: 11.3 months. Treatment-emergent adverse events (TEAEs; any grade) occurred in 120 patients (97.6%), and TEAEs grade ≥3 occurred in 91 patients (74.0%). TEAEs resulting in dose hold or dose reduction occurred in 44.7% and 9.8% of patients, respectively. CONCLUSION: The PRIMO study demonstrates significant activity and tolerability of duvelisib in patients with R/R PTCL, most notably in the AITL subgroup. This provides strong rationale for further development in PTCL, and more specifically in the subgroup of nodal T-follicular helper cell lymphoma.

PURPOSE: Acalabrutinib, a second-generation Bruton tyrosine kinase inhibitor, has efficacy in relapsed and refractory diffuse large B-cell lymphoma (DLBCL). The ACCEPT trial investigated the safety and efficacy of acalabrutinib in addition to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) in first-line therapy. METHODS: In this phase Ib/II non-randomized study, eligible patients were treatment naïve, aged 16 years or older with a histologic diagnosis of DLBCL. The primary end point of the trial was to determine the recommended phase II dose (RP2D) of acalabrutinib in combination with R-CHOP and assess the safety and overall response rate (ORR). RESULTS: Between 2017 and 2020, 38 patients were enrolled. Of those enrolled, seven were ineligible. Median age was 64 years (range, 24-80); 76% were stage III/IV; 55% International Prognostic Index ≥3. No dose-limiting toxicities were observed, and the RP2D of acalabrutinib was 100 mg twice daily. The most common grade ≥3 adverse events at RP2D were neutropenia (37%), febrile neutropenia (13%), and diarrhea (10%). Eighty-eight percent of patients received six cycles of R-CHOP. Age did not compromise treatment delivery. At the RP2D, 20/24 (83%) patients had a complete response and three (12.5%) a partial response (ORR, 96% [95% CI, 79 to 100]). With median 30-months follow-up, the 24-month progression-free survival was 95% (95% CI, 68 to 99), event-free survival was 90% (95% CI, 66 to 97), and overall survival was 96% (95% CI, 73 to 99). CONCLUSION: The combination of acalabrutinib with R-CHOP is well tolerated, including in those older than 65 years. High efficacy in DLBCL was observed, regardless of cell-of-origin subtype. These findings support further investigation of this combination in a randomized trial.

PURPOSE: In large B-cell lymphoma (LBCL), use of high-dose methotrexate (HD-MTX) to prevent CNS relapse (so-called CNS prophylaxis) remains controversial. International guidelines continue to recommend HD-MTX in patients deemed ultra high risk (UHR) because of a lack of robust data specific to these subgroups. This study was designed to examine the impact of HD-MTX specifically in UHR patients. METHODS: Data from two previous retrospective analyses were combined to produce a cohort of UHR patients (≥1 of the following criteria: CNS international prognostic index score 5-6; testicular, renal/adrenal, or breast involvement; ≥3 extranodal sites), treated with or without HD-MTX. The primary outcome was CNS relapse rate (isolated or concurrent with systemic relapse) measured from diagnosis with additional landmark analysis of all responding patients with no progression event at 6 months. RESULTS: Analyses were performed on 1,923 patients meeting UHR criteria. No significant difference in 3-year CNS relapse rate was observed between no HD-MTX (n = 1,051) versus HD-MTX patients (n = 872), including in multivariable analyses adjusting for baseline characteristics (3-year rate, 9.3% v 8.1%; adjusted hazard ratio [HR], 1.13 [95% CI, 0.82 to 1.57]). Analyses restricted to isolated CNS relapse also confirmed no difference (5.9% v 5.7%; adjusted HR, 1.03 [95% CI, 0.69 to 1.53]). In the landmark analysis (no HD-MTX n = 782, HD-MTX n = 773), no difference in 3-year CNS relapse was observed (6.7% v 6.6%, adjusted HR, 0.95 [95% CI, 0.62 to 1.44]). CONCLUSION: To our knowledge, this is the largest international comparative data set of patients with LBCL with UHR features showing no significant reduction in CNS relapse with HD-MTX in all UHR or in any individual subgroup. Despite inherent limitations of retrospective analyses, the data strongly support previous studies in suggesting HD-MTX prophylaxis has no meaningful benefit for most patients.

PURPOSE: Circulating tumor DNA (ctDNA) is emerging as a promising tool to monitor treatment response in large B-cell lymphoma (LBCL). Tracking tumor-specific phased variants (PVs) allows ultrasensitive detection of minimal residual disease (MRD) that may enhance the accuracy of response assessment. Previous studies have been constrained by small cohort size, retrospective design, or assays limited to a single commercial provider. PATIENTS AND METHODS: DIRECT was a prospective, multisite study evaluating the utility of ctDNA in patients with LBCL. We developed a lymphoma-customized, open-source, ctDNA assay and pipeline that captured hundreds of PVs per patient. Using landmark analysis, we evaluated the prognostic impact of PV-supported MRD at the end of first-line therapy (EoT). RESULTS: EoT PV-MRD status was available for 155 patients. After a median of 24.5 months, 2-year time to tumor progression (TTP) for patients with detectable versus undetectable PV-MRD was 42% versus 95%, respectively ( P < .001; hazard ratio [HR], 13.7). When restricted to patients receiving full-dose anthracycline-based immunochemotherapy, 2-year TTP was 45% versus 96%, respectively ( P < .001; HR, 15.4), outperforming conventional radiological response assessment (HRs, 6.9 for positron emission tomography v 16.9 for PV-MRD). The limit of detection with 95% confidence (LoD95) varied by more than two orders of magnitude across patients, underscoring the need to report patient-specific LoD95. Persistent PV-MRD in the absence of relapse was noted, including three of four patients with transformed follicular lymphoma, highlighting a potential caveat when interpreting positive PV-MRD . CONCLUSION: EoT PV-MRD enables sensitive and clinically meaningful response assessment in LBCL. It provides independent prognostic information, enhancing EoT response assessment beyond conventional radiologic assessment. Our findings support the incorporation of PV-MRD into clinical trials and routine management of diffuse LBCL.

Objectives: To assess the cost-effectiveness of extending the interval between monitoring blood tests beyond 3-monthly intervals during established treatment of adults prescribed low-dose weekly MTX (≤25 mg/week), LEF or SSZ. Methods: Published prognostic models that estimated the risk of stopping treatment due to abnormal blood test results during 5 years of established treatment were incorporated into a cost-effectiveness model. The consequences of having an extended monitoring period and a delay in stopping treatment was estimated by clinicians as the probability of someone having 1 of the 11 adverse events (AEs) that could be avoided with monitoring. The clinicians erred towards overestimating the risks. The costs and quality-adjusted life year loss of the AEs were sourced from recent National Institute of Health and Care Excellence appraisals or from targeted searches. Incremental net monetary benefit (iNMB) of 6-, 12- and 24-monthly monitoring, compared with three monthly monitoring was calculated for each drug conditional on risk decile. Results: Our analyses show that extending the duration between monitoring appointments is cost-effective in all scenarios, even in a pessimistic analysis, where the risks of all AEs were tripled, and the costs of some AEs were increased. In the base case, biennial monitoring was often most cost-effective although the iNMB between annual and biennial monitoring was often small. Conclusion: Extending the interval between monitoring blood tests appears to be cost-effective with annual monitoring producing consistently good results regardless of assumptions related to risks of AEs, risk decile or treatment.

The last decade has witnessed significant progress in the clinical management of patients with newly diagnosed primary central nervous system (CNS) diffuse large B-cell lymphoma (PCNS-DLBCL, hereafter referred to as PCNSL). Data from several clinical trials have demonstrated the potential for long-term remission in a proportion of patients, particularly those eligible for intensive multi-agent chemotherapy approaches. High-dose methotrexate (HD‑MTX)‑based induction regimens remain standard-of-care globally for both younger and older patients with newly diagnosed PCNSL. However, with clinical trial data demonstrating the efficacy of multiple regimens (differing in partner chemotherapy agents, hematological toxicity, and MTX dose density), but with few randomized comparisons, the optimal induction regimen remains unclear. Consolidation therapy is key to survival outcomes in PCNSL. Thiotepa-based autologous stem cell transplantation (TT-ASCT) has been widely adopted as the consolidation therapy of choice for patients ≤70 years. However, it is increasingly recognized that appropriately selected patients older than 70 years can also benefit from TT-ASCT consolidation. In parallel, declining rates of whole-brain radiotherapy (WBRT) have been observed due to significant risk of neurotoxicity, particularly in patients aged ≥60 years. This review summarises the contemporary clinical management of patients with newly diagnosed PCNSL. We focus on key diagnostic considerations, the landscape of evidence-based first-line treatments, and practical guidance for treatment selection and delivery. We also briefly discuss specific scenarios, including human immunodeficiency virus (HIV)-associated PCNSL and vitreoretinal involvement in the context of PCNSL.