Pierluigi Porcu

Advanced mycosis fungoides (MF) and Sézary syndrome (SS) are the most aggressive forms of cutaneous T‐cell lymphoma and remain associated with a poor prognosis and heterogeneous therapeutic approaches. Recent advances, including targeted therapies and improved transplant strategies, have substantially expanded treatment options, highlighting the need for updated international guidance integrating dermatologic, hematologic, and transplant perspectives. An international multidisciplinary panel convened by the European Hematology Association (EHA), the EORTC Cutaneous Lymphoma Tumours Group (EORTC‐CLTG), the International Society for Cutaneous Lymphoma (ISCL), and the EBMT Lymphoma Working Party reviewed the available evidence and developed consensus recommendations for the management of advanced MF and SS. Thirty international experts participated in the process. Recommendations address diagnostic work‐up, systemic therapies, treatment sequencing, combination strategies, and indications for allogeneic hematopoietic cell transplantation (allo‐HCT). The consensus supports a stage‐adapted and compartment‐oriented therapeutic approach. Immunomodulatory strategies remain central in advanced CTCL: extracorporeal photopheresis is commonly used as first‐line therapy in SS and in patients with significant blood involvement, while interferon‐α and retinoids are widely used in MF, often in combination with skin‐directed therapies. Mogamulizumab and brentuximab vedotin represent key options after prior systemic therapy, with differential activity across skin, blood, and nodal compartments. Combination approaches integrating systemic and skin‐directed treatments may improve response depth and durability. Practical treatment algorithms for advanced MF and SS are proposed to support therapeutic sequencing and multidisciplinary management. Allo‐HCT remains the only potentially curative treatment and should be considered early in selected patients with high‐risk disease features.

Large granular lymphocytic leukemia (LGLL) is an uncommon and likely under-diagnosed leukemia that causes severe neutropenia and anemia and can have profound effects on the quality of life for afflicted patients. Frequently associated with various auto-immune phenomena, LGLL is a paradigm for a highly interdisciplinary disease. Recent advances in our pathobiological understanding of LGLL, along with the development of novel agents, have stimulated a growing number of clinical trials and innovative approaches targeting this disease. Currently, the absence of uniform diagnostic and response criteria for LGLL results in significant heterogeneity in diagnosis and response assessment across studies. Furthermore, with the emergence of a variety of novel experimental therapeutics and an increasing number of clinical trials, it becomes critical to better define the key diagnostic, treatment and response parameters for this disease. The International LGLL Consortium was created to develop cross-disciplinary expert consensus on uniform diagnostic, treatment, and response criteria for LGLL suitable for both routine clinical use and interventional trials while facilitating cross-study comparisons. Utilizing an evidence-based framework, along with the international panel that comprises the LGLL Consortium, this report delineates the key criteria that will serve as a foundation for both the clinical management and future investigations in LGLL.

Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH)2/1, under investigation in non‐Hodgkin lymphomas (NHLs) and solid tumors. In vitro, it inhibits cytochrome P450 3A (CYP3A) and P‐glycoprotein (P‐gp) when combined with sensitive CYP3A or P‐gp substrates. This drug–drug interaction (DDI) sub‐study is part of the phase 1 trial of valemetostat monotherapy (DS3201‐A‐J101; NCT02732275), assessing the effect of valemetostat on the pharmacokinetics (PK) of sensitive CYP3A and P‐gp substrates midazolam and digoxin, respectively, in patients with relapsed or refractory NHL, and its safety and efficacy. Patients received two simultaneous single doses of midazolam and digoxin: once alone and once concomitantly with a daily 200 mg valemetostat dose in a 28‐day cycle. Of 24 enrolled patients, 15 and 16 were evaluable for PK analyses of midazolam and digoxin, respectively. Valemetostat co‐administration caused a slight decrease in midazolam maximum plasma concentration ( C _max ) (geometric least‐squares mean ratio [GMR], 0.966 [90% confidence interval (CI), 0.769–1.21]) and area under the plasma concentration–time curve up to the last quantifiable time (AUC _last ) (GMR, 0.87 [90% CI, 0.75–1.03]), increased digoxin C _max (GMR, 1.30 [90% CI, 1.07–1.57]), and AUC _last (GMR, 1.27 [90% CI, 1.06–1.52]). The overall safety and efficacy outcomes were similar to other studies. Valemetostat showed a manageable and tolerable safety profile, without clinically meaningful DDI with sensitive CYP3A substrates. Co‐administration of valemetostat and P‐gp substrates with a narrow therapeutic index may require careful monitoring and/or DDI risk management.

Human T-cell leukemia virus type 1 (HTLV-1), the first oncogenic human retrovirus, causes adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm of mature CD4+ T-cells that is incurable in most patients and is associated with a median survival of less than 1 year. HTLV-1 also causes inflammatory disorders, including HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. The estimated lifetime risks of ATLL and HAM/TSP in HTLV-1 carriers are 3–5% and 0.25–1.8%, respectively. Although there is uncertainty about other health effects of HTLV-1, a recent meta-analysis showed an association between HTLV-1 and cardiovascular, cerebrovascular, and metabolic diseases and a 57% increased risk of early mortality in HTLV-1 carriers, independent of ATLL or HAM/TSP. Furthermore, emerging studies in endemic areas show that outcomes for common cancers, such as cervical cancer and lymphoma (non-ATLL), are inferior in HTLV-1 carriers compared to publicly reported data. Thus, the impact of HTLV-1 may be greater and more diverse than currently understood. This review provides an outline of the prevalence and impact of HTLV-1 and associated disorders in the US, focused on—but not limited to—ATLL, with an emphasis on the social determinants of health that can affect the success of screening and prevention strategies. We also discuss the mechanisms by which HTLV-1 drives the pathogenesis of ATLL and potential strategies for early diagnosis and intervention. Finally, we conclude by suggesting approaches to designing and implementing community-informed research initiatives in HTLV-1 and ATLL.

The Human T-cell leukemia virus type 1 (HTLV-1), the first oncogenic human retrovirus, causes adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm of mature CD4+ T cells that is incurable in most patients and is associated with a median survival of less than 1 year. HTLV-1 also causes inflammatory disorders, including HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. The estimated lifetime risks of ATLL and HAM/TSP in HTLV-1 carriers are 3-5% and 0.25-1.8%, respectively. Although there is uncertainty about other health effects of HTLV-1, a recent meta-analysis showed association between HTLV-1 and cardiovascular, cerebrovascular, and metabolic diseases, and a 57% increased risk of early mortality, in HTLV-1 carriers, independent of ATLL or HAM/TSP. Furthermore, emerging studies in endemic areas show that outcomes for common cancers, such as cervical cancer and lymphoma (non-ATLL) are inferior in HTLV-1 carriers compared to publicly reported data. Thus, the public health impact of HTLV-1 may be greater and more diverse than currently understood and the full spectrum and prevalence of HTLV-1-associated disorders need to be better investigated, in both endemic and non-endemic areas. Furthermore, the mechanisms by which HTLV-1 functions as a disease driver or modifier need to be studied. This review provides an outline of the prevalence and impact of HTLV-1 and associated disorders in the US, focused on - but not limited to - ATLL, with emphasis on education gaps and other social determinants of health that can affect the success of screening and prevention strategies, especially in immigrant communities at risk. We also discuss mechanisms by which HTLV-1 drives the pathogenesis of ATLL, and potential strategies for early diagnosis and intervention. Finally, we conclude by suggesting approaches to design and implement community-informed research initiatives in HTLV-1 and ATLL.

Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse–enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse.

Clinical trials with single-agent venetoclax/ABT-199 (anti-apoptotic BCL2 inhibitor) revealed that diffuse large B-cell lymphoma (DLBCL) is not solely dependent on BCL2 for survival. Gaining insight into pathways/proteins that increase venetoclax sensitivity or unique vulnerabilities in venetoclax-resistant DLBCL would provide new potential treatment avenues. Therefore, we generated acquired venetoclax-resistant DLBCL cells and evaluated these together with intrinsically venetoclax-resistant and -sensitive DLBCL lines. We identified resistance mechanisms, including alterations in BCL2 family members that differed between intrinsic and acquired venetoclax resistance and increased dependencies on specific pathways. Although combination treatments with BCL2 family member inhibitors may overcome venetoclax resistance, RNA-sequencing and drug/compound screens revealed that venetoclax-resistant DLBCL cells, including those with TP53 mutation, had a preferential dependency on oxidative phosphorylation. Mitochondrial electron transport chain complex I inhibition induced venetoclax-resistant, but not venetoclax-sensitive, DLBCL cell death. Inhibition of IDH2 (mitochondrial redox regulator) synergistically overcame venetoclax resistance. Additionally, both acquired and intrinsic venetoclax-resistant DLBCL cells were similarly sensitive to inhibitors of transcription, B-cell receptor signaling, and class I histone deacetylases. These approaches were also effective in DLBCL, follicular, and marginal zone lymphoma patient samples. Our results reveal there are multiple ways to circumvent or overcome the diverse venetoclax resistance mechanisms in DLBCL and other B-cell lymphomas and identify critical targetable pathways for future clinical investigations.