Precision Medicine in Non-Hodgkin Lymphoma: Advances in BTK Inhibition, CD30-Directed Antibody–Drug Conjugates, and HDAC-Mediated Epigenetic Therapy with Pirtobrutinib, Brentuximab Vedotin, and Belinostat

Abstract

Non-Hodgkin lymphoma (NHL) encompasses a biologically diverse group of malignancies for which the integration of precision medicine has markedly reshaped therapeutic strategies. Recent advances in molecular profiling, target identification, and drug development have led to the introduction of highly selective agents capable of overcoming resistance mechanisms and improving outcomes in relapsed or refractory disease. This review highlights three targeted therapies—pirtobrutinib, brentuximab vedotin, and belinostat—and their evolving roles in modern NHL management. Pirtobrutinib, a next-generation, non-covalent Bruton tyrosine kinase (BTK) inhibitor, demonstrates preserved activity in patients previously treated with covalent BTK inhibitors (BTKi), addressing a critical unmet need in B-cell lymphomas. Brentuximab vedotin, an antibody–drug conjugate targeting CD30, has significantly improved therapeutic precision by delivering cytotoxic agents directly to lymphoma cells and has become a central component of treatment for CD30-expressing NHL subtypes. Belinostat, a broad-spectrum histone deacetylase (HDAC) inhibitor, offers a mechanistically distinct epigenetic approach, particularly in peripheral T-cell lymphomas (PTCL), where conventional chemotherapy has limited efficacy. Together, these agents exemplify three complementary paradigms of precision oncology in NHL: kinase signaling inhibition, antigen-directed cytotoxic delivery, and epigenetic modulation. This review synthesizes current evidence, clinical trial data, and future perspectives regarding the integration of pirtobrutinib, brentuximab vedotin, and belinostat into evolving treatment paradigms. Cumulatively, these therapies illustrate both the progress and the ongoing challenges of biomarker-driven treatment in NHL, including resistance mechanisms, toxicity management, optimal therapeutic sequencing, and variability in evidence maturity across targeted strategies. While pirtobrutinib and brentuximab vedotin are supported by increasingly robust clinical evidence in selected lymphoma subtypes, the role of belinostat remains constrained by modest response rates and limited randomized data, underscoring the continued need for biomarker refinement and more precisely individualized therapeutic approaches in NHL precision medicine.

1. Introduction

NHL comprises a biologically and clinically heterogeneous group of lymphoid malignancies arising from B-cell, T-cell, or natural killer (NK)-cell lineages and represents one of the most common hematologic cancers worldwide [1,2,3]. This diversity reflects the complexity of lymphocyte ontogeny, encompassing distinct differentiation states, genomic alterations, and microenvironmental dependencies that, in combination, shape disease behavior and therapeutic responsiveness. Advances in modern classification systems integrating molecular, genetic, and immunophenotypic features have substantially refined diagnostic precision and clarified the prognostic and therapeutic relevance of individual subtypes [3,4,5], with ongoing efforts to further bridge biological insights and disease taxonomy [6]. In parallel, contemporary clinical practice has evolved toward subtype-specific, guideline-driven management frameworks, as reflected in recommendations from organizations such as the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) [1,2]. As a result, NHL is increasingly conceptualized not as a single disease entity but as a spectrum of biologically defined malignancies characterized by distinct molecular vulnerabilities and therapeutic targets [7,8,9], supported by expanding therapeutic platforms including immunotherapy, antibody-based strategies, and cellular therapies [10,11].

Despite these advances, conventional cytotoxic chemotherapy—most notably anthracycline-based regimens such as CHOP and rituximab-containing R-CHOP—has historically constituted the backbone of treatment for many aggressive B-cell lymphomas [12,13]. While curative outcomes are achievable in a proportion of patients, particularly in diffuse large B-cell lymphoma (DLBCL), relapse and refractory disease remain major clinical challenges [13,14,15,16]. These limitations are driven in part by underlying biological heterogeneity, clonal evolution under treatment pressure, and the emergence of resistant subclones, which together constrain the durability of non-specific cytotoxic approaches [5,15,17]. Moreover, clinically relevant molecular subtypes—including activated B-cell-like (ABC), germinal center B-cell-like (GCB), and double-hit lymphomas—exhibit distinct therapeutic sensitivities and prognoses, further underscoring the need for biologically informed treatment strategies [18,19,20,21,22]. Contemporary treatment paradigms increasingly incorporate targeted agents and novel combinations, aiming to improve outcomes beyond conventional chemotherapy backbones [23,24].

The increasing availability of high-throughput molecular technologies, including next-generation sequencing (NGS), transcriptomic profiling, and epigenetic analyses, has enabled deeper characterization of lymphoma biology and the identification of actionable therapeutic targets [25], with growing global implementation even in resource-variable settings [26]. Among these, dysregulation of B-cell receptor (BCR) signaling has emerged as a central pathogenic mechanism in many B-cell malignancies, promoting tumor survival, proliferation, and interaction with the tumor microenvironment [27,28]. Targeting this pathway has led to the development of Bruton’s tyrosine kinase (BTK) inhibitors, which have become integral components of modern lymphoma therapy [29,30,31]. However, resistance to first-generation covalent BTKi frequently arises, most commonly through mutations affecting the BTK C481 binding site, alongside alternative signaling adaptations [27,28,30]. These challenges have catalyzed the development of next-generation agents such as pirtobrutinib, a highly selective non-covalent BTK inhibitor capable of overcoming C481-mediated resistance and demonstrating clinically meaningful activity in heavily pretreated populations [32,33,34].

Complementing kinase inhibition, antibody–drug conjugates (ADCs) represent a distinct therapeutic strategy that couples antigen specificity with targeted cytotoxic delivery. Brentuximab vedotin, an anti-CD30 ADC linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE), exemplifies this approach and has demonstrated significant efficacy in CD30-expressing lymphomas [35,36]. Although initially developed in Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, its application has expanded to selected NHL subtypes, supported by both biological rationale and randomized clinical evidence in CD30-positive PTCL and emerging evidence in other NHL settings [35,36]. More broadly, ADCs and related antibody-based platforms—including bispecific T-cell engagers—are reshaping therapeutic algorithms across lymphoma subtypes [11,37]. Nevertheless, variability in antigen expression and toxicity profiles continues to influence optimal patient selection and clinical use.

In parallel, epigenetic dysregulation has emerged as a critical driver of lymphomagenesis, particularly in PTCL, where outcomes remain poor with conventional therapies [2,38]. Aberrant histone modification and chromatin remodeling contribute to oncogenic transcriptional programs and resistance mechanisms, providing a strong rationale for epigenetic-targeted therapies. HDAC inhibitors such as belinostat have demonstrated clinical activity in relapsed or refractory PTCL, although response rates remain modest and are supported primarily by non-randomized data, highlighting the need for improved patient selection and rational combination strategies [38,39,40]. Ongoing research is focused on integrating epigenetic agents with immunotherapy and targeted therapies to enhance therapeutic efficacy [41,42].

Beyond tumor-intrinsic alterations, the tumor microenvironment plays a pivotal role in disease progression, immune evasion, and therapeutic resistance through complex interactions between malignant cells and surrounding stromal and immune components [20,33,34]. These insights have contributed to the development of immunotherapeutic approaches, including immune checkpoint inhibition and cellular therapies, which have transformed outcomes in selected patient populations [20,43,44]. Advances in imaging and response assessment, particularly molecular imaging techniques, further support precision management and treatment monitoring [45]. Additionally, circulating tumor DNA (ctDNA) has emerged as a promising tool for non-invasive disease monitoring and dynamic assessment of treatment response, although its routine clinical application remains under active investigation [46,47].

Together, these developments reflect a paradigm shift from empiric, chemotherapy-based treatment toward precision medicine approaches that integrate molecular biology, disease subtype, and patient-specific factors into therapeutic decision-making [19,20,25]. However, important challenges persist, including the identification of robust predictive biomarkers, the management of primary and acquired resistance, optimal sequencing and combination of therapies, and disparities in access to advanced diagnostics and targeted agents across healthcare systems, with economic considerations increasingly influencing real-world implementation [7,8,9,48].

Against this evolving backdrop, pirtobrutinib, brentuximab vedotin, and belinostat were selected because they represent three mechanistically distinct yet complementary paradigms of precision medicine in NHL: targeted kinase signaling inhibition, antigen-directed antibody–drug conjugation, and epigenetic modulation. Although these agents differ substantially in disease context, biomarker dependence, and level of supporting clinical evidence, together they illustrate the heterogeneity of biomarker-driven therapeutic development across NHL subtypes and the differing degrees of clinical maturity among contemporary targeted strategies. Pirtobrutinib reflects the evolution of rationally designed next-generation kinase inhibitors developed to overcome acquired resistance mechanisms; brentuximab vedotin exemplifies the successful integration of biomarker-directed ADC therapy into randomized treatment frameworks in selected CD30-positive lymphomas; and belinostat highlights both the promise and the current limitations of epigenetic therapies supported primarily by single-arm clinical evidence. Together, these agents provide a focused lens through which to examine both the progress and the remaining challenges of precision oncology in NHL.

This narrative review aims to deliver a comprehensive and critically integrated overview of precision medicine in NHL, emphasizing the clinical and biological rationale underpinning these therapeutic strategies. By synthesizing mechanistic insights, pivotal clinical trial evidence, and real-world considerations, this work contextualizes the evolving role of pirtobrutinib, brentuximab vedotin, and belinostat within contemporary, guideline-informed treatment frameworks, while highlighting ongoing challenges and future opportunities in the optimization of personalized care for patients with lymphoid malignancies.

Relevant literature was identified through selective searches of the PubMed and Scopus databases focusing on English-language publications published between 2006 and April 2026. The reviewed literature included pivotal clinical trials, randomized studies, registration-supporting investigations, meta-analyses, major review articles, and clinically informative real-world studies relevant to pirtobrutinib, brentuximab vedotin, belinostat, and precision medicine approaches in NHL. Additional references were incorporated based on their clinical relevance, translational significance, or contribution to the contextual interpretation of evolving therapeutic strategies, resistance mechanisms, biomarker development, and treatment sequencing in lymphoma.

The schematic figures presented in this manuscript were developed by the authors using graphical design software that may include artificial intelligence–supported visualization tools. All scientific concepts, data interpretation, and final graphical compositions were independently evaluated, revised, and approved by the authors, who assume full responsibility for the accuracy, integrity, and originality of the presented material.

Figure 1 provides a schematic overview of treatment selection in NHL, integrating key clinical trial evidence according to biomarker status, disease subtype, and line of therapy.

2. Pirtobrutinib

Pirtobrutinib (LOXO-305) is a highly selective, next-generation, non-covalent (reversible) inhibitor of BTK, developed to overcome key limitations of first- and second-generation covalent BTKi such as ibrutinib and acalabrutinib [49,50]. Unlike covalent inhibitors that irreversibly bind the C481 residue of BTK, pirtobrutinib maintains activity independently of this binding site, thereby overcoming one of the most common mechanisms of acquired resistance—namely C481 mutations [51,52,53]. This pharmacologic distinction is clinically relevant in heavily pretreated populations with relapsed or refractory NHL and chronic lymphocytic leukemia (CLL), where resistance to covalent BTKi frequently limits long-term disease control [54,55]. Mechanistically, resistance to BTK inhibition reflects both on-target mutations and adaptive pathway reprogramming, underscoring the need for next-generation inhibitors such as pirtobrutinib [56,57].

BTK is a central component of BCR signaling, regulating downstream pathways including NF-κB, PI3K/AKT, and MAPK, which in combination drive malignant B-cell proliferation, survival, and microenvironmental interactions [58,59,60]. Pirtobrutinib exerts potent and selective inhibition of BTK activity, demonstrating comparable efficacy against both wild-type and mutant BTK in preclinical models [61,62,63]. Its improved kinome selectivity relative to earlier BTKi reduces off-target effects, likely contributing to the favorable safety and tolerability profile observed in clinical studies [64], a feature emphasized in early clinical evaluations and regulatory approval analyses [65,66,67]. Figure 2 illustrates the mechanism of action of pirtobrutinib.

The first clinical evidence supporting pirtobrutinib was generated in the phase I/II BRUIN trial (NCT03740529), a multicenter, open-label, dose-escalation and expansion study evaluating its activity across multiple relapsed or refractory B-cell malignancies [32,69]. This study enrolled heavily pretreated patients, many of whom had prior exposure to covalent BTKi and other targeted therapies, with eligibility generally requiring at least one prior line of systemic treatment and, for the mantle cell lymphoma (MCL) cohort, prior covalent BTKi exposure. Notably, no maximum tolerated dose was identified, and the recommended phase II dose of 200 mg once daily was selected based on pharmacokinetic and pharmacodynamic considerations rather than dose-limiting toxicity [70,71], highlighting a potentially favorable pharmacologic profile relative to earlier BTKi.

Within BRUIN, pirtobrutinib demonstrated clinically meaningful activity across NHL subtypes. In MCL, ORRs of approximately 50–52% were observed in patients previously treated with covalent BTKi, with durable responses reported in heavily pretreated populations [72]. These findings were further supported in the MCL registration cohort (n ≈ 120), which reported an ORR of 50%, CR rate of 13%, and median duration of response (DoR) of 8.3 months, forming the basis for regulatory approval in this setting. Real-world and expanded-access data further support these observations, demonstrating activity in routine clinical practice [73]. Importantly, this cohort consisted largely of patients refractory to their last BTK inhibitor, underscoring the potential role of pirtobrutinib in a high-risk population characterized by limited therapeutic options. However, interpretation of these findings should recognize the single-arm design and absence of randomized comparator data.

Additional subgroup analyses from BRUIN extended these findings across disease contexts. In follicular lymphoma (FL), ORRs of approximately 50–52% (CR ~16.7%) with a median DoR of ~10.2 months were reported in patients with a median of three prior lines of therapy [74]. Similarly, in marginal zone lymphoma (MZL), response rates approached 50–55% with encouraging durability [75]. In the Richter transformation (RT) subgroup—an aggressive and biologically distinct entity—pirtobrutinib demonstrated antitumor activity and manageable tolerability despite the historically poor prognosis associated with this condition [76,77]. While these data suggest broad activity across both indolent and aggressive lymphoma subtypes, interpretation should be tempered by the single-arm design, limited sample sizes in certain cohorts, and potential for selection bias inherent to early-phase studies. Compared with antibody–drug conjugates or cellular immunotherapies, pirtobrutinib offers the practical advantage of oral administration and relatively predictable toxicity management, although response durability may remain more limited in biologically aggressive disease settings.

In parallel, the phase III BRUIN MCL-321 trial (NCT04662255) is evaluating pirtobrutinib versus investigator’s choice of covalent BTK inhibitor in previously treated, BTKi-naïve MCL, with progression-free survival (PFS) as the primary endpoint [78]. This global, randomized study specifically addresses an earlier-line population not exposed to prior BTK inhibition and is expected to provide confirmatory evidence while helping define the positioning of pirtobrutinib relative to first-generation BTKi. Comparative analyses with other advanced therapies, including CAR-T approaches, further highlight the need to contextualize pirtobrutinib within an increasingly competitive therapeutic landscape [79]. In contrast to CAR-T therapy, which may achieve deeper and potentially more durable remissions in selected patients, pirtobrutinib provides a more accessible and less logistically intensive treatment option, particularly for older or medically frail patients who may not be candidates for cellular therapy.

In CLL/SLL, pirtobrutinib has demonstrated ORRs exceeding 80% in patients previously exposed to covalent BTKi, with durable responses and favorable PFS outcomes [80,81]. These findings were corroborated in the randomized phase III BRUIN CLL-321 trial, where pirtobrutinib significantly improved PFS compared with investigator’s choice therapy, reducing the risk of disease progression or death by approximately 46% [82], with median PFS approaching 20 months in heavily pretreated populations [83]. Additional comparative data from BRUIN CLL-314 suggest response rates comparable to or slightly higher than those of ibrutinib (~87% vs. 78.5%) in both treatment-naïve and relapsed settings [84], although the clinical significance of incremental ORR differences remains uncertain in the absence of mature overall survival (OS) data. These findings reinforce the evolving role of noncovalent BTK inhibition as a strategy designed specifically to address acquired resistance associated with earlier-generation covalent BTKi.

The safety profile of pirtobrutinib appears favorable across available studies. Rates of class-associated toxicities such as atrial fibrillation, bleeding, and hypertension appear lower than those observed with first-generation BTKi [85,86,87]. Common adverse events include fatigue, diarrhea, and neutropenia, which are generally low grade and manageable with supportive care [33,88,89]. This improved tolerability is likely related to enhanced kinase selectivity and reduced off-target inhibition [90]. Nonetheless, class-wide effects such as platelet dysfunction and infection risk remain relevant considerations in BTK inhibitor therapy [91,92]. Longer follow-up is required to more fully characterize long-term and cumulative toxicities, particularly in the context of continuous therapy, although patient-reported outcomes suggest acceptable tolerability over time [93]. From a comparative perspective, the toxicity profile of pirtobrutinib differs substantially from that observed with antibody–drug conjugates or HDAC inhibitors, where peripheral neuropathy or hematologic toxicity may more significantly limit prolonged treatment exposure.

In the context of NHL, pirtobrutinib is being integrated into an increasingly complex therapeutic landscape that includes CAR-T cell therapies, bispecific antibodies, and other targeted agents. Its activity in patients previously treated with CAR-T therapy or stem cell transplantation suggests a potential role in salvage or bridging strategies [94]. However, prospective comparative data remain limited, and optimal sequencing relative to cellular therapies is not yet clearly defined. Importantly, while kinase inhibition offers mechanistically precise targeting of B-cell receptor signaling, adaptive resistance through pathway reactivation or bypass signaling remains a persistent therapeutic challenge.

Combination strategies represent a key area of ongoing investigation and reflect a rational attempt to enhance response depth and overcome resistance mechanisms [95,96,97,98]. Combination-based therapeutic strategies are increasingly being explored to enhance the depth and durability of response associated with targeted NHL therapies. Early-phase studies are evaluating pirtobrutinib in combination with anti-CD20 monoclonal antibodies, BCL2 inhibitors such as venetoclax, and emerging immunotherapeutic agents [95]. For example, pirtobrutinib has demonstrated promising activity in combination with venetoclax, supported by the complementary inhibition of B-cell receptor signaling and BCL-2-mediated antiapoptotic pathways, which may synergistically promote lymphoma cell death and overcome resistance mechanisms observed with BTK inhibitor monotherapy. These approaches are biologically supported by complementary targeting of survival pathways (e.g., BTK–BCL2 axis) and modulation of tumor–immune interactions. Early-phase clinical studies evaluating BTK inhibitor–venetoclax combinations have reported encouraging activity in relapsed or refractory B-cell malignancies, including improved response depth and potential enhancement of minimal residual disease negativity, supporting continued exploration of chemotherapy-free targeted regimens [96,97,98]. However, metabolic adaptation and persistence mechanisms, including reprogramming of cellular energetics, may influence resistance and response durability [99]. While preliminary data suggest potential synergy, robust randomized evidence is still lacking, and overlapping toxicities as well as optimal scheduling require careful evaluation [100]. Early clinical experience further suggests that rationally designed combination regimens may improve response durability and therapeutic efficacy, although larger randomized studies remain necessary to define their optimal positioning within evolving NHL treatment algorithms. Compared with epigenetic therapies such as belinostat, these kinase inhibitor–based combinations may offer more biomarker-defined mechanistic targeting, although long-term resistance suppression remains uncertain.

Outside hematologic malignancies, there is currently no established role for pirtobrutinib in solid tumors such as breast cancer. Although BTK signaling has been implicated in tumor microenvironment modulation and immune regulation, clinical evidence supporting BTK inhibition in solid tumors remains limited and inconclusive [101,102].

From a broader perspective, pirtobrutinib exemplifies a rational approach to overcoming targeted therapy resistance through structure-guided drug design. Its ability to inhibit both wild-type and mutant BTK—including common resistance-associated C481 substitutions—positions it as a promising therapeutic option for patients who have progressed on prior BTKi [103,104]. However, emerging resistance mechanisms—including additional BTK mutations and activation of alternative signaling pathways—highlight the need for continued research into combination strategies and biomarker-driven patient selection [105]. In contrast to antibody–drug conjugates, which rely on antigen expression and intracellular payload delivery, kinase inhibition provides continuous suppression of oncogenic signaling but may be more vulnerable to adaptive pathway rewiring and clonal evolution over time.

Importantly, much of the current evidence relies on surrogate endpoints such as ORR and PFS. While these endpoints provide early signals of efficacy, their translation into OS benefit remains to be fully established [106]. Variability in trial design, patient populations, and comparator regimens further complicates cross-study comparisons, underscoring the need for cautious interpretation and the importance of randomized confirmatory trials. Moreover, differences in disease biology across NHL subtypes limit direct extrapolation of efficacy outcomes between indolent and aggressive lymphomas.

Pirtobrutinib represents an important advance in the management of B-cell malignancies, particularly in the relapsed or refractory NHL setting. Its activity in BTK inhibitor–resistant disease, favorable safety profile, and emerging role across multiple disease subtypes—including MCL, FL, MZL, and RT—support its growing relevance within precision oncology. Nevertheless, the level of supporting evidence varies across disease settings, and several conclusions continue to rely primarily on early-phase or single-arm studies [107,108,109].

Kinase inhibition with pirtobrutinib represents a mechanistically precise and clinically active therapeutic paradigm, particularly valuable for overcoming acquired resistance to earlier BTKi, although questions regarding long-term durability, optimal sequencing, and resistance evolution remain incompletely resolved. Compared with antibody–drug conjugate therapy and epigenetic modulation, pirtobrutinib currently benefits from a relatively more mature biomarker rationale and broader integration into contemporary NHL treatment algorithms, but continued randomized validation remains essential. Ongoing randomized trials, longer follow-up, and biomarker-guided strategies will therefore be essential to more clearly define its optimal positioning within evolving treatment algorithms and increasingly combination-based therapeutic paradigms.

Table 1. TEAEs and management strategies for pirtobrutinib according to [33,72,110]. All abbreviations employed are defined in the text in the Abbreviations Section.

TEAE	Frequency/Severity	Timing/Clinical Features	Recommended Management
Infections	Common; severity variable, including grade ≥ 3 events	May occur at any time during treatment; includes respiratory and viral infections, with higher clinical relevance in heavily pretreated or immunocompromised patients	Monitor closely for fever and infection symptoms; initiate prompt diagnostic workup and antimicrobial therapy as indicated; consider dose interruption for severe infection.
Hemorrhage/bruising/contusion	Common overall; major hemorrhage uncommon	Usually low-grade bruising or contusion, but serious bleeding can occur; risk may increase with anticoagulants, antiplatelet agents, or thrombocytopenia	Review bleeding risk and concomitant medications; monitor clinically; interrupt treatment for significant bleeding and resume only after risk–benefit reassessment.
Cytopenias (neutropenia, anemia, thrombocytopenia)	Common; may be grade ≥ 3, especially neutropenia	Often detected during routine monitoring; may contribute to infection risk, fatigue, or bleeding	Perform serial CBC monitoring; use dose interruption or reduction for clinically significant cytopenias; provide growth factor support or transfusion as appropriate.
Fatigue	Common; usually grade 1–2	Frequently reported across BRUIN cohorts; may accumulate over time and may be multifactorial	Evaluate reversible causes, optimize hydration and nutrition, encourage activity pacing, and consider dose modification for persistent grade ≥ 3 fatigue.
Gastrointestinal toxicity (diarrhea, nausea, abdominal symptoms)	Common; mostly grade 1–2	Usually early or intermittent during therapy; generally manageable with supportive care	Use hydration, dietary adjustment, and antidiarrheal/antiemetic therapy as needed; consider dose modification for persistent or severe symptoms.
Musculoskeletal and constitutional symptoms (musculoskeletal pain, arthralgia, headache)	Common; usually low grade	May emerge during ongoing therapy; typically non-limiting but can affect quality of life	Symptomatic treatment with analgesics and supportive care; reassess if persistent or function-limiting.
Dyspnea/cough	Common; usually grade 1–2, occasionally clinically significant	May reflect treatment-related symptoms, infection, anemia, or underlying cardiopulmonary disease	Evaluate for infection, anemia, and disease progression; manage symptomatically; interrupt therapy if severe or unexplained.
Cardiac arrhythmias (including atrial fibrillation/flutter)	Uncommon; grade ≥ 3 events relatively infrequent	May occur during treatment, particularly in patients with prior cardiac disease or risk factors	Assess baseline cardiovascular history; monitor clinically for palpitations or rhythm disturbance; interrupt and manage according to severity.
Rash and other cutaneous events	Less common; usually mild to moderate	Typically develops during treatment exposure and is often manageable	Use emollients, antihistamines, or topical corticosteroids when needed; interrupt treatment for severe skin toxicity.
Laboratory abnormalities/biochemical changes	Variable; may include grade ≥ 3 hematologic laboratory abnormalities	Usually detected on routine monitoring rather than by symptoms alone	Regular laboratory surveillance and correction of reversible abnormalities; manage according to severity and associated clinical findings.
Rare serious events (severe infection, major bleeding, cardiac events)	Rare but clinically important	More relevant in older, heavily pretreated, or comorbid populations	Prompt evaluation, treatment interruption, and specialist-directed management when severe toxicity is suspected.

summarizes treatment-emergent adverse events (TEAEs) and their management strategies for pirtobrutinib, while

Table 2. Major pivotal clinical trials and selected emerging studies of pirtobrutinib in non-Hodgkin lymphoma. All abbreviations employed are defined in the text in the Abbreviations Section.

Trial/Study	Population	Cancer Setting	Design	Combination	Key Findings	Inclusion/ Eligibility Criteria
BRUIN phase 1/2 (NCT03740529) [33]	R/R B-cell malignancies; key NHL cohort: MCL after prior covalent BTKi	R/R NHL (primarily MCL)	Multicenter, open-label, phase 1/2	Monotherapy	ORR ~52% in cBTKi-pretreated MCL; durable responses	≥1 prior therapy; prior covalent BTKi required for MCL cohort
BRUIN MCL registration cohort [111]	n = 120 R/R MCL; median ~3 prior lines	R/R MCL after ≥2 prior lines incl. BTKi	Open-label, single-arm	Monotherapy	ORR 50%, CR 13%, median DoR 8.3 months; basis for approval	Prior BTKi required; majority refractory
BRUIN MCL-321 (NCT04662255) [78]	Previously treated, BTKi-naïve MCL	R/R MCL (earlier-line)	Global, randomized, phase III	Monotherapy vs. investigator’s choice BTKi	Ongoing confirmatory trial; primary endpoint: PFS	≥1 prior therapy; no prior BTKi
BRUIN (follicular lymphoma cohort) [74]	R/R FL; median ~3 prior lines	R/R indolent NHL (FL)	Phase 1/2 cohort analysis	Monotherapy	ORR ~52%, CR ~16.7%; median DoR ~10 months	Relapsed/refractory FL
BRUIN (marginal zone lymphoma cohort) [75]	R/R MZL	R/R indolent NHL (MZL)	Phase 1/2 cohort analysis	Monotherapy	ORR ~55%; durable responses	Prior therapy required
BRUIN (Richter transformation cohort) [112]	RT (DLBCL-type)	Aggressive lymphoma	Phase 1/2 subgroup analysis	Monotherapy	Encouraging activity in high-risk population	Prior therapies allowed
GATE1 (NCT06522386) [95]	Previously untreated MCL	Frontline MCL	Phase II	Pirtobrutinib + rituximab + venetoclax	Ongoing triplet targeted strategy	Untreated MCL
Pirtobrutinib + venetoclax (NCT05529069) [96]	Relapsed/refractory MCL	R/R MCL	Phase II	Combination	Ongoing; BTK–BCL2 targeting	Prior therapy required
Pirtobrutinib + rituximab (NCT06263491) [97]	Newly diagnosed low/intermediate-risk MCL	Frontline MCL	Phase II	Combination	Ongoing chemo-free strategy	Untreated MCL
Pirtobrutinib + glofitamab (NCT06252675) [98]	Relapsed/refractory mantle cell lymphoma	R/R MCL	Phase II	Combination	Ongoing exploratory regimen	Relapsed/refractory disease

BRUIN-derived publications [33,74,75,107,108] correctly share NCT03740529.

outlines the major pivotal clinical trials and selected emerging studies of pirtobrutinib in NHL.

3. Brentuximab Vedotin

Brentuximab vedotin is an ADC composed of a chimeric anti-CD30 monoclonal antibody linked to the microtubule-disrupting agent MMAE, representing a targeted cytotoxic strategy designed to selectively deliver chemotherapy to CD30-expressing malignant cells [113,114]. CD30, a member of the tumor necrosis factor receptor superfamily, is highly expressed in several NHL subtypes, including systemic anaplastic large cell lymphoma (sALCL) and subsets of other PTCLs, while exhibiting more limited expression in normal tissues [115,116]. CD30 is also characteristically expressed in classical Hodgkin lymphoma, which contributed to the early clinical development of brentuximab vedotin; however, its current role in NHL is particularly relevant in CD30-positive T-cell lymphomas and selected B-cell lymphoma settings [117]. At the same time, the biologic and prognostic role of CD30 appears context-dependent and may vary according to histology, cell of origin, and microenvironmental features, particularly in DLBCL [118].

Mechanistically, brentuximab vedotin binds to CD30 on the tumor cell surface, undergoes internalization, and traffics to lysosomes, where the protease-cleavable linker releases MMAE into the cytoplasm [119]. MMAE subsequently binds to tubulin, disrupting microtubule dynamics, inducing cell-cycle arrest at the G2/M phase, and ultimately triggering apoptotic cell death [120,121]. In addition to direct cytotoxicity, a bystander effect has been described, whereby MMAE diffuses into adjacent cells, potentially enhancing antitumor activity in heterogeneous tumors with variable CD30 expression [122]. Furthermore, emerging evidence suggests immunomodulatory effects, including enhanced antigen presentation and modulation of the tumor microenvironment, although the clinical relevance of these mechanisms remains incompletely defined [123]. These multimodal properties likely contribute to the broader-than-expected activity of brentuximab vedotin in diseases with variable CD30 expression, while also complicating the interpretation of CD30 as a strict predictive biomarker. Figure 3 depicts the mechanism of action of brentuximab vedotin.

The initial clinical development of brentuximab vedotin included pivotal phase II studies in relapsed or refractory Hodgkin lymphoma and sALCL. In Hodgkin lymphoma, early trials demonstrated substantial activity after autologous stem cell transplantation (ASCT), supporting regulatory development and establishing proof of concept for CD30-targeted ADC therapy [125,126,127,128,129]. More directly relevant to NHL, the phase II Study 2 (NCT00866047) in relapsed or refractory systemic ALCL demonstrated ORRs of 86%, CR rates of 57%, and a median DoR of 12.6 months in heavily pretreated patients [35]. These findings established brentuximab vedotin as a major therapeutic advance in relapsed CD30-positive NHL, particularly PTCL. However, the single-arm design of these early studies and the absence of comparator arms necessitate cautious interpretation, particularly regarding long-term survival benefit. Compared with kinase inhibitors or epigenetic therapies, brentuximab vedotin demonstrated relatively high response rates in biomarker-selected populations, although the durability of benefit remains influenced by disease biology, antigen heterogeneity, and prior treatment exposure.

Subsequent randomized trials further expanded the role of brentuximab vedotin in NHL. The phase III ECHELON-2 (NCT01777152) trial compared brentuximab vedotin combined with cyclophosphamide, doxorubicin, and prednisone (BV-CHP) versus standard CHOP in previously untreated CD30-positive PTCL. This study demonstrated significant improvements in both PFS and OS, establishing BV-CHP as a new standard of care in this setting [36]. Extended follow-up confirmed durable clinical benefit, with sustained PFS and OS advantages at 5 years [36,130]. Importantly, the magnitude of benefit was greatest in systemic ALCL, emphasizing the biologic heterogeneity of PTCL and raising questions regarding the generalizability of these findings to subtypes with lower or more heterogeneous CD30 expression. Contemporary expert analyses further stress that the efficacy of “CHOP-plus” approaches is not uniform across PTCL histologies and should not be interpreted as biologically equivalent across the entire PTCL spectrum [131,132]. Additional subtype-specific molecular features may further influence therapeutic response [133]. Emerging evidence further suggests that predictive biomarkers beyond CD30 expression alone may contribute to therapeutic responsiveness, including tumor microenvironment composition, immune-cell infiltration patterns, cytokine-mediated signaling, and variability in intracellular payload processing and MMAE sensitivity. These observations support the concept that CD30 expression should be interpreted within a broader biologic and immunologic context rather than as an isolated binary biomarker. In contrast to BTK inhibition, where resistance is frequently mediated by pathway-specific molecular alterations, resistance to ADC therapy may additionally involve antigen modulation, impaired internalization, altered payload trafficking, or microenvironment-mediated survival signaling.

Hodgkin lymphoma studies such as ECHELON-1 and AETHERA additionally demonstrated the broader clinical activity of brentuximab vedotin in CD30-positive lymphoid malignancies [117,134]. These trials provided important contextual evidence supporting the therapeutic validity of CD30 targeting, although their direct applicability to NHL treatment algorithms remains limited. Consequently, current NHL-focused interest centers primarily on PTCL, CTCL, and selected LBCL settings rather than Hodgkin lymphoma-specific frontline or post-transplant strategies [135,136,137,138,139].

In relapsed or refractory NHL, particularly PTCL and other CD30-positive entities, brentuximab vedotin has shown meaningful activity both as monotherapy and in combination regimens. The phase III ALCANZA (NCT01578499) trial in CD30-positive cutaneous T-cell lymphoma (CTCL) demonstrated superior durable response rates compared with physician’s choice, confirming improved disease control in this population [140]. Final analyses further confirmed the durability of response and consistent clinical benefit across subgroups, with a manageable safety profile and no new safety signals [140,141]. Additionally, the phase III ECHELON-3 (NCT04404283) trial extended the role of brentuximab vedotin into relapsed/refractory LBCL, where its combination with lenalidomide and rituximab significantly improved OS, as well as PFS and ORR, in transplant- or CAR-T–ineligible patients [142]. These findings were supported by subsequent analyses confirming efficacy across clinically relevant subgroups and a manageable safety profile [142,143]. Together, these studies highlight an expanding role beyond classical CD30-high T-cell lymphomas, although patient selection remains critical and the biologic basis for benefit in lower-CD30-expression settings remains incompletely resolved. Contemporary lymphoma management frameworks increasingly position brentuximab vedotin within broader NHL treatment algorithms that also incorporate CAR-T therapy, bispecific antibodies, and subtype-specific salvage strategies [144]. Compared with epigenetic therapies such as belinostat, brentuximab vedotin currently benefits from stronger randomized clinical evidence and clearer integration into frontline treatment paradigms, although its applicability remains dependent on antigen expression and subtype-specific biology.

Additional NHL-focused studies evaluating combinations with bendamustine, gemcitabine-based regimens, platinum-containing salvage therapy, and checkpoint inhibitors have reported encouraging response rates, although these findings are derived primarily from early-phase trials with limited sample sizes [145,146,147,148,149,150,151]. However, the heterogeneity of PTCL and variability in CD30 expression complicate interpretation of these data, underscoring the need for biomarker-informed approaches to optimize patient selection. Emerging translational investigations are increasingly evaluating immune-related biomarkers, tumor-associated macrophage composition, T-cell exhaustion markers, and spatial immune architecture as potential determinants of response and resistance. Such findings may eventually facilitate more refined biologic stratification and individualized therapeutic sequencing in CD30-positive NHL.

Combination strategies involving brentuximab vedotin and immune checkpoint inhibitors have also generated interest due to potentially complementary mechanisms of action [152]. Combination-based therapeutic strategies are increasingly being explored to enhance the depth and durability of response associated with targeted NHL therapies. In particular, brentuximab vedotin has shown encouraging activity in combination with immune checkpoint inhibition, including nivolumab-based regimens, where immunogenic cell death induced by the antibody–drug conjugate may augment antitumor immune responses and potentially enhance T-cell–mediated cytotoxicity. Mechanistically, MMAE-mediated tumor cell death may promote antigen release and immune activation, thereby providing a biologic rationale for synergy with PD-1 blockade. Although much of the initial clinical experience originated in Hodgkin lymphoma [153,154], emerging studies in B-cell lymphomas suggest that these combinations may broaden activity beyond classical CD30-high diseases [155]. Early-phase clinical studies have reported encouraging response rates and durable remissions in selected relapsed or refractory lymphoma populations, supporting continued investigation of these immunotherapy-based combination approaches. Nevertheless, additive toxicity, cost, and the absence of mature comparative NHL-specific data continue to limit routine adoption across all settings. These findings illustrate the broader evolution of ADC therapy from simple targeted cytotoxic delivery toward increasingly immunologically integrated therapeutic strategies.

The safety profile of brentuximab vedotin is well characterized and largely consistent across studies. The most common adverse events include peripheral neuropathy, neutropenia, fatigue, and gastrointestinal symptoms [134]. Peripheral neuropathy is dose-dependent and may be cumulative, often necessitating dose modification or discontinuation [156]. Hematologic toxicity, particularly neutropenia, is also common, especially in combination regimens, and may require growth factor support [157]. Rare but serious adverse events include progressive multifocal leukoencephalopathy and pancreatitis, although these are infrequent [158]. Real-world reports continue to underscore the clinical importance of neurologic toxicity, particularly in patients with pre-existing risk factors or treatment-related vulnerabilities [159]. In special populations, including older or frail patients and those with major comorbidities, tolerability considerations may substantially affect regimen selection and dose intensity [160,161]. Overall, the toxicity profile is manageable but requires careful monitoring, particularly in the context of prolonged therapy or multidrug combinations. Importantly, the toxicity spectrum of ADC therapy differs mechanistically from that of kinase inhibitors or HDAC inhibitors, with peripheral neuropathy representing a particularly distinctive limitation of MMAE-containing ADCs.

In the broader context of precision oncology, brentuximab vedotin exemplifies the successful application of ADC technology in hematologic malignancies. Its efficacy is closely linked to CD30 expression, although the threshold of expression required for clinical benefit remains uncertain. Notably, responses have been observed even in tumors with low or heterogeneous CD30 expression, suggesting that additional mechanisms, including bystander effects and microenvironmental interactions, may contribute to therapeutic activity [162]. This observation complicates the use of CD30 as a strict predictive biomarker and highlights the need for more refined biomarker strategies. Emerging evidence suggests that additional biomarkers beyond CD30 expression alone may influence responsiveness to brentuximab vedotin, including tumor microenvironment composition, immune-cell infiltration patterns, and variability in intracellular payload processing [15,19,20,41,118,131]. It also suggests that CD30 expression should be interpreted not simply as a binary marker, but within a broader biologic framework that includes spatial heterogeneity, immune contexture, and disease subtype. Although these biomarkers remain investigational, they may contribute to improved therapeutic stratification and resistance prediction in future NHL treatment paradigms. Relative to kinase inhibition, which targets intracellular signaling pathways, ADC therapy offers a therapeutically attractive strategy capable of combining biologic specificity with direct cytotoxic delivery, although dependence on antigen expression and payload-related toxicity remain important limitations.

In non-hematologic malignancies, including breast cancer, brentuximab vedotin has not demonstrated a defined clinical role. While CD30 expression has been reported in a minority of solid tumors, including certain breast cancer subtypes, clinical evidence supporting the efficacy of CD30-targeted therapy in this context remains limited and largely investigational [163]. Consequently, its use remains confined to CD30-positive lymphoid malignancies.

From a critical perspective, the development of brentuximab vedotin illustrates both the strengths and limitations of targeted cytotoxic strategies. Randomized NHL-focused trials such as ECHELON-2, ALCANZA, and ECHELON-3 have clearly established its value in selected settings [164,165,166], yet variability in CD30 expression, underlying disease biology, and treatment context limits straightforward generalization across NHL subtypes. Similarly, although numerous combination strategies appear promising, many remain supported mainly by phase I/II datasets, and their long-term impact on survival, toxicity burden, and therapeutic sequencing is not yet fully defined. Compared with pirtobrutinib, which primarily addresses resistance through continuous kinase suppression, or belinostat, which exerts broader epigenetic reprogramming effects, brentuximab vedotin occupies an intermediate therapeutic paradigm characterized by high initial activity but persistent dependence on antigen biology and payload tolerability.

Furthermore, the reliance on surrogate endpoints such as PFS in several key trials underscores the need for longer follow-up to determine whether observed benefits consistently translate into meaningful improvements in OS [167]. Differences in trial design, patient populations, prior therapies, and comparator regimens further complicate cross-study comparisons, necessitating cautious interpretation of the evidence base. Some NHL settings now also require comparison against rapidly evolving standards incorporating checkpoint inhibitors, CAR-T therapy, or other novel immunotherapeutic platforms, which may further reshape the relative positioning of brentuximab vedotin.

Brentuximab vedotin represents a major advance in the treatment of CD30-positive NHL, with demonstrated efficacy across multiple disease settings and lines of therapy, particularly in systemic ALCL, other CD30-positive PTCLs, CTCL, and selected LBCL populations. Its integration into frontline regimens, salvage strategies, and combination approaches reflects its versatility as a targeted therapeutic agent. However, ongoing studies are needed to refine patient selection, optimize combination strategies, better define its role relative to competing immunotherapeutic approaches, and further clarify its place within evolving, biomarker-driven NHL treatment algorithms [166,167,168,169,170,171,172]. Population-based analyses from the brentuximab vedotin era and continuing real-world studies will also be important for understanding long-term outcomes beyond clinical trial populations [173].

Antibody–drug conjugate therapy with brentuximab vedotin represents one of the most clinically validated targeted approaches currently available in NHL, particularly within CD30-positive T-cell lymphomas, although challenges related to resistance biology, biomarker refinement, and toxicity optimization continue to define important areas for future investigation.

Table 3. TEAEs and management strategies for brentuximab vedotin according to [35,174,175]. All abbreviations employed are defined in the text in the Abbreviations Section.

TEAE	Frequency/Severity	Timing/Clinical Features	Recommended Management
Peripheral neuropathy	Common; cumulative; usually grade 1–2, but may reach grade ≥ 3	A key toxicity across NHL studies. In ECHELON-2, peripheral neuropathy occurred in 52% and was predominantly sensory, with median onset at 2 months; in ECHELON-3, it occurred in 27%, with median onset at 3 months.	Regular neurologic assessment; dose delay, reduction, or discontinuation for persistent or severe neuropathy; supportive care for neuropathic symptoms.
Hematologic toxicity (neutropenia, anemia, thrombocytopenia, febrile neutropenia)	Common; neutropenia may be severe, especially in combination regimens	In ECHELON-2, febrile neutropenia occurred in 18% with A + CHP versus 15% with CHOP. In ECHELON-3, dose delays were commonly driven by neutropenia (23%) and thrombocytopenia (8%).	CBC monitoring before each cycle; growth factor support when indicated; dose modification; transfusion or infection-directed management as needed; urgent treatment of febrile neutropenia.
Gastrointestinal toxicity (nausea, diarrhea, constipation, vomiting, abdominal pain, decreased appetite)	Common; mostly grade 1–2	In ECHELON-2, nausea and diarrhea were among the adverse reactions seen more often with A + CHP; in ECHELON-3, diarrhea occurred in 31% of patients receiving BV-based therapy.	Antiemetics, hydration, dietary support, bowel regimen, and dose adjustment for persistent or severe symptoms.
Fatigue/asthenia	Common; generally low grade, occasionally grade ≥ 3	Fatigue is a recurrent toxicity in BV-treated NHL populations. In ECHELON-2, fatigue/asthenia was more frequent with A + CHP than CHOP; in ECHELON-3, fatigue occurred in 46% of BV-treated patients.	Assess reversible contributors, optimize nutrition and hydration, encourage activity pacing, and consider dose modification for persistent grade ≥ 3 fatigue.
Pyrexia and infections	Common to serious; severity variable	In ECHELON-2, pyrexia was more frequent with A + CHP. In ECHELON-3, serious adverse reactions included pneumonia (21%), COVID-19 (13%), sepsis (9%), and febrile neutropenia (7%).	Prompt infection workup, antimicrobial therapy when indicated, supportive care, and treatment interruption for serious infectious events.
Respiratory toxicity/pulmonary events	Less common but potentially severe	May present with dyspnea, cough, pneumonitis, interstitial changes, or infectious pneumonia. Pulmonary toxicity is included in the prescribing information warnings; pneumonia was a major serious AE in ECHELON-3.	Evaluate urgently to distinguish infection, drug toxicity, and disease progression; interrupt treatment; provide supportive care; discontinue in severe or recurrent cases.
Cutaneous toxicity (rash, pruritus)	Common; usually mild to moderate	Rash is among the common adverse reactions reported with BV-containing regimens, including ECHELON-3.	Emollients, antihistamines, topical corticosteroids if needed, and treatment interruption for severe skin toxicity.
Infusion-related reactions	Uncommon to less common; occasionally severe	Typically occur during or shortly after infusion; manifestations may include chills, nausea, dyspnea, pruritus, pyrexia, or cough.	Slow or interrupt infusion, provide symptomatic treatment, consider premedication in selected patients, and discontinue for severe recurrent reactions.
Hepatotoxicity	Uncommon but clinically relevant; occasionally severe	Can occur after the first dose or on rechallenge, with transaminase and/or bilirubin elevation.	Monitor liver function tests before and during therapy; delay, reduce, or discontinue treatment for clinically significant hepatotoxicity.
Serious neurologic and opportunistic events (including PML)	Rare but potentially life-threatening	The prescribing information carries a boxed warning for JC virus-associated PML; onset may occur at variable times after treatment initiation.	Immediate evaluation of new neurologic symptoms; hold therapy if PML is suspected; permanently discontinue if confirmed.
Rare serious systemic events (pancreatitis, severe dermatologic reactions, gastrointestinal complications, hyperglycemia)	Rare but clinically important	These events are less frequent but are highlighted in the prescribing information as important safety concerns.	Prompt evaluation and supportive management; interrupt or discontinue treatment according to severity and clinical context.

summarizes TEAEs and their management strategies for brentuximab vedotin, while

Table 4. Major pivotal clinical trials and studies of brentuximab vedotin in non-Hodgkin lymphoma. All abbreviations employed are defined in the text in the Abbreviations Section.

Trial/Study	Population	Cancer Setting	Design	Combination	Key Findings	Inclusion/ Eligibility Criteria
Study 2 (NCT00866047) [35]	Relapsed/refractory sALCL (n = 58)	Relapsed/refractory	Phase II, open-label, single-arm, multicenter	Brentuximab vedotin	ORR 86%, CR 57%; median DoR 12.6 months; durable responses in heavily pretreated patients	Histologically confirmed sALCL; ≥1 prior systemic therapy; relapsed or refractory disease; prior auto-HSCT allowed
ECHELON-2 (NCT01777152) [36]	Previously untreated CD30+ PTCL, including sALCL, PTCL-NOS, AITL (n = 452)	Front-line	Phase III, randomized, double-blind, active-controlled	Brentuximab vedotin + CHP vs. CHOP	Improved PFS (48.2 vs. 20.8 months; HR 0.71) and OS benefit; established BV + CHP as standard in CD30+ PTCL	CD30 expression ≥10%; untreated PTCL; ECOG 0–1; adequate organ function
ALCANZA (NCT01578499) [140]	CD30+ cutaneous T-cell lymphoma (CTCL), including mycosis fungoides and pcALCL (n = 131)	Relapsed/refractory	Phase III, randomized, open-label, multicenter	Brentuximab vedotin vs. physician’s choice (methotrexate or bexarotene)	Durable response ≥4 months: 56.3% vs. 12.5%; superior disease control vs. standard options	Prior systemic therapy; CD30+ MF or pcALCL; candidates for systemic treatment
ECHELON-3 (NCT04404283) [142]	Relapsed/refractory LBCL, including DLBCL and HGBL (n = 230)	Relapsed/refractory	Phase III, randomized, double-blind, placebo-controlled	Brentuximab vedotin + lenalidomide + rituximab vs. placebo + lenalidomide + rituximab	Improved OS (13.8 vs. 8.5 months; HR 0.63); PFS and ORR benefit (64.3% vs. 41.5%)	≥2 prior lines; transplant/CAR-T ineligible; ECOG 0–2; measurable disease

ALCANZA is usually grouped under NHL because CTCL/pcALCL are T-cell NHL subtypes.

outlines the major pivotal clinical trials and selected emerging studies of brentuximab vedotin in NHL.

4. Belinostat

Belinostat is a pan-HDAC inhibitor belonging to the class of epigenetic modulators that alter gene expression through reversible acetylation of histone and non-histone proteins, thereby influencing chromatin structure and transcriptional activity [176,177]. HDAC enzymes play a central role in regulating gene expression by removing acetyl groups from lysine residues on histones, leading to chromatin condensation and transcriptional repression. Dysregulation of HDAC activity has been implicated in lymphomagenesis, particularly in T-cell lymphomas, where aberrant epigenetic silencing contributes to malignant transformation and disease progression [178,179,180]. By inhibiting multiple HDAC isoforms, belinostat promotes histone acetylation, chromatin relaxation, reactivation of tumor suppressor genes, and induction of cell-cycle arrest and apoptosis in malignant cells [181,182,183]. This mechanistic breadth distinguishes belinostat from pathway-specific kinase inhibitors, but it also contributes to a broader and less predictable spectrum of biologic effects [184,185].

Beyond its direct epigenetic effects, belinostat influences cellular processes including modulation of cell-cycle regulators, inhibition of angiogenesis, and alteration of immune responses within the tumor microenvironment [186]. Preclinical studies suggest that HDAC inhibition may enhance antigen presentation and increase susceptibility to immune-mediated killing, providing a rationale for combination strategies with immunotherapies [187]. However, the pleiotropic nature of HDAC inhibition may narrow the therapeutic window and complicate translation into consistently durable clinical benefit. Broader reviews of HDAC inhibitor development in lymphoma have emphasized this duality, highlighting both mechanistic promise and the difficulty of identifying patients most likely to benefit [188,189,190]. Figure 4 presents the mechanism of action of belinostat.

The clinical development of belinostat in NHL was established primarily in relapsed or refractory PTCL, a heterogeneous group of aggressive malignancies with historically poor outcomes and limited treatment options. The pivotal phase II BELIEF trial (NCT00865969) evaluated belinostat in patients with relapsed or refractory PTCL (n = 129), including PTCL-NOS, angioimmunoblastic T-cell lymphoma (AITL), and ALK-negative ALCL, and demonstrated an ORR of approximately 26%, including CRs in a subset of patients [40]. The median DoR was 13.6 months, indicating that durable remissions may be achievable in selected patients [192]. Responses were observed across multiple PTCL subtypes, suggesting activity beyond a single histologic category. A post hoc subgroup analysis also demonstrated maintained clinical activity in patients with baseline thrombocytopenia, with manageable hematologic toxicity [192]. These findings supported the regulatory approval of belinostat in relapsed or refractory PTCL [193,194,195]. Compared with kinase inhibition or antibody–drug conjugate therapy, belinostat represents a broader and less biomarker-defined therapeutic paradigm, in which clinical activity reflects modulation of transcriptional and epigenetic programs rather than inhibition of a single dominant oncogenic driver.

Importantly, however, belinostat should be distinguished from agents supported by randomized phase III or broader comparative evidence. In contrast to therapies such as brentuximab vedotin in CD30-positive PTCL, belinostat remains supported primarily by a single-arm phase II registration study, with no randomized phase III trials to date [40,192]. This substantially limits the strength of comparative evidence and constrains its precise positioning within modern treatment algorithms. Recent policy-focused analyses have also used belinostat as an example of the broader challenge posed by accelerated approvals that are not followed rapidly by confirmatory trials, raising important questions regarding evidence maturity and long-term regulatory confidence [196]. From an integrative perspective, this evidentiary gap places belinostat in a less firmly established position than brentuximab vedotin, which benefits from randomized NHL-focused trial data, or pirtobrutinib, which is increasingly supported by subtype-specific prospective studies.

Interpretation of the BELIEF trial therefore requires caution. Response rates, while clinically meaningful in a difficult-to-treat population, remain modest compared with some newer targeted, antibody-based, or cellular approaches [40]. Moreover, the heterogeneity of PTCL—including major differences in molecular drivers, epigenetic architecture, and microenvironmental dependencies—likely contributes to variable treatment response [178,179,180,197]. Contemporary reviews of PTCL biology and management increasingly stress that this heterogeneity is central to therapeutic decision-making and may partly explain why epigenetic therapies demonstrate activity in some patients yet remain difficult to optimize across broader populations [198,199,200,201]. The absence of validated biomarker-driven patient selection further limits the ability to identify the subgroups most likely to benefit from HDAC inhibition. Emerging translational studies are increasingly investigating whether epigenetic signatures, histone acetylation profiles, chromatin-remodeling alterations, and tumor microenvironment characteristics may eventually support more refined therapeutic stratification. In particular, recurrent alterations involving epigenetic regulators and transcriptional programs in PTCL subtypes such as AITL may partly explain differential sensitivity to HDAC inhibition, although these observations remain investigational and are not yet clinically validated.

Earlier phase I studies, such as NCT00274651, established the safety, tolerability, and recommended dosing schedule of belinostat in patients with advanced NHL, demonstrating preliminary antitumor activity across T-cell lymphoma subtypes [202]. These foundational data informed subsequent phase II development and supported the dosing strategy used in relapsed/refractory PTCL. Later clinical characterization suggested that certain subtypes, particularly AITL, may derive relatively greater benefit, although these observations remain exploratory rather than definitive [203]. This subtype signal is biologically plausible given the epigenetic vulnerability of selected PTCL entities, but it remains less clinically actionable than CD30-directed selection for brentuximab vedotin or BTK pathway targeting for pirtobrutinib.

Subsequent studies have explored belinostat in combination with chemotherapy and other targeted agents in an effort to improve efficacy. Early-phase trials combining belinostat with CHOP (Bel-CHOP), including the phase I/II NCT01839097 study, demonstrated encouraging response rates, with ORRs exceeding 80% in some PTCL cohorts and an acceptable safety profile [204]. While these results suggest potential synergy between epigenetic modulation and cytotoxic chemotherapy, the lack of randomized phase III data limits definitive conclusions regarding survival benefit. Differences in trial design, patient selection, and endpoint definitions further complicate comparisons with established regimens. Thus, these data support further investigation of HDAC inhibitor-based combinations but do not yet establish belinostat-containing regimens as broadly evidence-equivalent to randomized standards.

Additional combination strategies have evaluated belinostat with cytotoxic and epigenetic agents. Studies combining belinostat with carboplatin and paclitaxel (NCT00421889) demonstrated manageable toxicity and preliminary antitumor activity in relapsed or refractory aggressive lymphomas [205,206,207]. Similarly, dual epigenetic-targeting strategies, such as belinostat combined with azacitidine (NCT00351975), have shown early evidence of synergistic activity, supporting the rationale for epigenetic combination approaches [205,208]. Broader HDAC-based combination strategies remain under investigation in early-phase studies, with limited but evolving clinical data [209,210,211]. Preclinical work has further suggested synergy between HDAC inhibition and proteasome inhibition, PLK1 inhibition, Src-pathway targeting, geranylgeranyl transferase inhibition, and other biologically complementary approaches [212,213,214,215]. These findings are mechanistically intriguing, but most have not yet translated into robust clinical evidence. In comparison with pirtobrutinib-based or brentuximab vedotin-based combinations, belinostat combinations remain more exploratory, reflecting both the complexity of epigenetic modulation and the difficulty of defining optimal partner agents.

The safety profile of belinostat is generally consistent with other HDAC inhibitors but appears comparatively favorable in certain respects. Common adverse events include nausea, fatigue, anemia, and thrombocytopenia, which are typically manageable with supportive care and dose adjustments [216,217]. Notably, belinostat has been associated with a lower incidence of severe thrombocytopenia than some other HDAC inhibitors, which may facilitate combination therapy [218]. However, hematologic toxicity remains a significant concern, particularly in heavily pretreated patients, and requires close monitoring. Clinical overviews of PTCL pharmacotherapy have generally positioned belinostat as one of the more tolerable epigenetic agents in this setting, although with efficacy that remains moderate and supported primarily by non-randomized evidence [219]. Compared with brentuximab vedotin, belinostat does not have the same characteristic burden of cumulative peripheral neuropathy; however, its more modest response rates and less clearly defined predictive framework limit its precision-oncology impact.

Cardiac toxicity, including QT prolongation, has been reported with HDAC inhibitors, although the incidence with belinostat appears relatively low [220,221]. Nevertheless, baseline and periodic electrocardiographic monitoring is recommended, particularly in patients with preexisting cardiac risk factors. Additionally, hepatic metabolism via UGT1A1 necessitates caution in patients with impaired liver function, and dose adjustments may be required [222,223]. Pharmacogenetic considerations may therefore be relevant in individualized dosing, particularly in patients with reduced UGT1A1 activity [224].

In the broader context of precision oncology, belinostat represents a distinct therapeutic paradigm focused on epigenetic reprogramming rather than direct targeting of oncogenic signaling pathways. While this approach offers the theoretical advantage of modulating multiple oncogenic processes simultaneously, it also introduces challenges related to specificity, response predictability, and mechanistic attribution [225]. Unlike kinase inhibitors, where treatment selection may be anchored to a defined actionable alteration, there are currently no validated predictive biomarkers for routine clinical selection of patients most likely to benefit from belinostat. This remains a major limitation to its integration into biomarker-driven treatment algorithms. Emerging investigations are exploring whether epigenetic signatures, histone acetylation patterns, molecular alterations affecting chromatin remodeling pathways, and immune-related microenvironmental features may eventually improve prediction of therapeutic responsiveness. Similarly, tumor microenvironment interactions and immune-cell infiltration patterns are increasingly being investigated as potential modulators of sensitivity and resistance to HDAC inhibition. Although these biomarkers remain investigational, they may contribute to improved therapeutic stratification and resistance prediction in future NHL treatment paradigms. Even when candidate biomarkers are proposed, however, their relevance may be disease-specific and not directly translatable across lymphoma subtypes [226].

In non-hematologic malignancies, including breast cancer, belinostat has been evaluated in early-phase studies, but clinical activity has been modest and inconsistent [227]. Although epigenetic dysregulation is recognized across many solid tumors, the translation of HDAC inhibition into meaningful clinical benefit has been limited, and its role outside hematologic malignancies remains investigational.

From a critical standpoint, the clinical development of belinostat illustrates both the therapeutic promise and the limitations of epigenetic strategies in lymphoma. Although durable responses can be achieved in a subset of patients with PTCL, ORRs remain modest, and the absence of randomized comparative trials precludes definitive conclusions regarding its relative efficacy within the broader treatment landscape [228]. Interpretation of available data is further complicated by heterogeneity in trial populations, prior lines of therapy, and underlying disease biology, which together limit cross-study comparability and reinforce the need for more refined, biomarker-driven patient selection. Real-world and anecdotal experience confirms that prolonged disease control is possible in selected patients, but such cases remain exceptional rather than predictive of routine outcomes [229]. Compared with pirtobrutinib and brentuximab vedotin, belinostat currently occupies a more selective and later-line role, particularly for patients in whom tolerability, prior treatment exposure, and lack of alternative options shape therapeutic decision-making.

The reliance on surrogate endpoints such as ORR in pivotal studies reinforces the importance of longer-term follow-up to better define the impact of belinostat on PFS and OS outcomes [163,230]. In parallel, the incorporation of belinostat into combination regimens introduces additional complexity related to cumulative toxicity, optimal sequencing, and cost-effectiveness, all of which must be balanced against potential improvements in clinical efficacy. More broadly, outcomes analyses in PTCL suggest that participation in clinical trials and access to newer agents may improve survival, but the relative contribution of belinostat specifically remains difficult to isolate from the expanding therapeutic landscape [231].

Ongoing research is therefore increasingly focused on identifying molecular and epigenetic biomarkers predictive of response to HDAC inhibition, as well as on developing rational combinations with immunotherapy and other targeted agents to enhance antitumor activity and overcome resistance mechanisms [232]. Preclinical studies also indicate that resistance to HDAC inhibition may create new therapeutic vulnerabilities, suggesting that adaptive resistance itself could become a basis for rational salvage strategies [233]. Within this evolving framework, belinostat remains a mechanistically distinct but comparatively less strongly validated option in relapsed or refractory PTCL, exerting its effects through HDAC inhibition and subsequent modulation of chromatin architecture and gene transcription [234,235]. This rationale is supported by the epigenetically dysregulated landscape of PTCL, characterized by recurrent alterations in chromatin-modifying genes and substantial transcriptional heterogeneity across molecular subtypes [236,237]. In contrast to the more target-defined paradigms represented by BTK inhibition and CD30-directed ADC therapy, belinostat provides a broader epigenetic intervention that may be particularly relevant in biologically heterogeneous PTCL, but this same breadth also complicates patient selection and resistance prediction.

Clinically, belinostat is associated with a manageable safety profile and favorable tolerability relative to intensive chemotherapy, supporting its use particularly in heavily pretreated or more vulnerable patient populations [238,239]. At the same time, the rapidly evolving NHL therapeutic landscape underscores the potential of HDAC inhibitor-based combination strategies to augment immune-mediated antitumor responses and address resistance pathways [240,241]. Despite these advances, the overall efficacy of belinostat as monotherapy remains limited, with modest response rates and a persistent lack of validated predictive biomarkers to guide optimal patient selection [238,242]. Moreover, the absence of randomized phase III evidence continues to constrain its definitive positioning within treatment algorithms, underscoring the need for prospective, biomarker-driven studies to more precisely define its role in precision oncology frameworks [239,242].

Epigenetic modulation with belinostat represents a biologically compelling but clinically less mature NHL therapeutic paradigm compared with kinase inhibition and antibody–drug conjugate therapy, with its future value likely dependent on biomarker refinement, rational combinations, and prospective validation in molecularly defined PTCL subgroups.

Table 5. TEAEs and management strategies for belinostat according to [40,243]. All abbreviations employed are defined in the text in the Abbreviations Section.

TEAE	Frequency/Severity	Timing/Clinical Features	Recommended Management
Gastrointestinal toxicity (nausea, vomiting, decreased appetite, diarrhea, constipation, abdominal pain)	Common; mostly grade 1–2	Usually early during treatment; may reduce oral intake and impair tolerability	Antiemetics, hydration, dietary support, bowel regimen, and dose delay/reduction for persistent or severe symptoms
Fatigue	Common; usually grade 1–2, occasionally grade ≥ 3	May emerge early and accumulate over cycles; often multifactorial	Assess reversible causes, optimize supportive care, and consider dose modification for persistent grade ≥ 3 fatigue
Hematologic toxicity (anemia, thrombocytopenia, neutropenia, febrile neutropenia)	Common; clinically significant in some patients	May occur during early or subsequent cycles, especially in heavily pretreated patients	Regular CBC monitoring, dose interruption/reduction, transfusional support, and prompt management of febrile neutropenia or severe cytopenias
Pyrexia and infections	Common to less common; severity variable	Fever may be isolated or associated with infection, particularly in cytopenic patients	Prompt evaluation for infection, supportive care, antimicrobial therapy when indicated, and treatment interruption for serious events
Respiratory and fluid-related events (dyspnea, cough, peripheral edema)	Common; occasionally grade ≥ 3	May reflect treatment effect, infection, anemia, comorbidity, or disease progression	Clinical assessment, supportive management, and treatment interruption with further workup for severe symptoms
Cutaneous toxicity (rash, pruritus)	Usually mild to moderate	Develops during treatment exposure; generally manageable	Emollients, antihistamines, topical corticosteroids if needed, and treatment interruption for severe skin toxicity
Laboratory abnormalities (hypokalemia, elevated LDH, other biochemical changes)	Usually mild to moderate; occasionally clinically relevant	Often detected on routine monitoring	Serial laboratory monitoring, electrolyte replacement, and correction of contributing factors
Cardiovascular events (QT prolongation, hypotension, dizziness)	Less common but clinically relevant	May occur during infusion or early cycles; risk increased by electrolyte imbalance or cardiac comorbidity	Review concomitant drugs, correct electrolytes, monitor at-risk patients, and interrupt treatment for symptomatic or severe events
Hepatotoxicity	Uncommon but potentially severe	May present with elevated liver enzymes or clinical liver dysfunction	Monitor liver function tests before and during therapy; interrupt or discontinue treatment for significant hepatic toxicity
Rare serious events (tumor lysis syndrome, multisystem toxicity)	Rare but potentially life-threatening	More likely early in treatment, particularly in patients with high tumor burden	Risk assessment, prophylaxis in high-risk patients, close monitoring, and immediate supportive management with treatment interruption if suspected
Infusion-related and other less frequent general events (chills, headache, phlebitis, infusion-site pain)	Usually low grade	Typically occur during or shortly after infusion	Symptomatic treatment, local supportive care, and infusion interruption/slowing if clinically indicated

summarizes TEAEs and their management strategies for belinostat, while

Table 6. Major pivotal clinical trials and key clinical studies of belinostat in non-Hodgkin lymphoma. All abbreviations employed are defined in the text in the Abbreviations Section.

Trial/Study	Population	Cancer Setting	Design	Combination	Key Findings	Inclusion/ Eligibility Criteria
BELIEF (NCT00865969) [40]	Relapsed/refractory PTCL (n = 129), including PTCL-NOS, AITL, ALK−ALCL; subset with thrombocytopenia (n ≈ 38)	Relapsed/refractory	Phase II, open-label, single-arm, multicenter (with post hoc subgroup analysis)	Belinostat monotherapy	ORR 25.8%, CR 10.8%; median DoR 13.6 months; clinically meaningful activity in heavily pretreated PTCL; subset analysis: maintained activity (~15–20% ORR) in patients with thrombocytopenia with manageable hematologic toxicity	≥1 prior systemic therapy; histologically confirmed PTCL; measurable disease; ECOG 0–2; adequate organ function; platelet count < 100 × 109/L permitted in subset
Bel-CHOP Phase I/II combination study (NCT01839097) [204]	Relapsed/refractory aggressive NHL, including PTCL and DLBCL	Relapsed/refractory	Phase I/II, open-label, dose-escalation and expansion	Belinostat + CHOP (Bel-CHOP)	Acceptable safety profile; high response rates in PTCL cohorts (ORR > 80% in some subsets); supports combination strategies	Untreated or relapsed aggressive NHL; adequate organ function; ECOG 0–2; dose-limiting toxicity assessment in escalation phase
Early phase study (NCT00274651) [202]	Relapsed/refractory T-cell lymphoma and other NHL subtypes	Relapsed/refractory	Phase I, open-label, dose-escalation	Belinostat monotherapy	Demonstrated safety, tolerability, and preliminary antitumor activity; established recommended dosing schedule	Advanced NHL after prior therapy; measurable disease; adequate marrow, hepatic, and renal function
Belinostat + carboplatin/paclitaxel (NCT00421889) [207]	Relapsed/refractory aggressive lymphomas (including PTCL and DLBCL)	Relapsed/refractory	Phase I/II	Combination (chemotherapy backbone)	Manageable toxicity; preliminary antitumor activity	Relapsed/refractory NHL; adequate organ function
Belinostat + azacitidine (NCT00351975) [208]	T-cell lymphomas (PTCL)	Relapsed/refractory	Phase I/II	Combination (epigenetic therapy)	Early evidence of synergistic activity via dual epigenetic modulation	Relapsed/refractory PTCL; measurable disease
Belinostat-based HDAC combinations (various early-phase studies) [209,210,211]	Advanced lymphomas (various NHL subtypes)	Relapsed/refractory	Early phase	Combination (epigenetic/targeted)	Exploratory strategies; limited clinical data	Advanced NHL; prior therapies allowed

outlines the major pivotal clinical trials and selected key clinical studies of belinostat in NHL.

5. Advancing Frontiers in Non-Hodgkin Lymphoma: Future Directions and Emerging Approaches

The therapeutic landscape of NHL is undergoing substantial transformation driven by advances in molecular biology, immunotherapy, and precision oncology. Increasingly, NHL is understood not as a single entity but as a spectrum of molecularly defined diseases shaped by distinct genetic, epigenetic, and microenvironmental determinants [244,245]. Although targeted agents such as pirtobrutinib, brentuximab vedotin, and belinostat have improved outcomes in selected settings, their optimal integration remains constrained by incomplete biomarker frameworks, disease heterogeneity, evolving resistance patterns, and the rapidly changing therapeutic landscape shaped by CAR-T-cell therapy and bispecific antibodies [5,246]. Consequently, the transition from empiric treatment algorithms toward truly biologically guided strategies remains an ongoing, rather than fully realized, objective [33,247].

Advances in molecular profiling technologies—including NGS, single-cell transcriptomics, and spatial analysis—have enabled increasingly granular characterization of tumor heterogeneity [99,248,249]. These approaches are refining disease classification by linking genomic alterations with functional and spatial context, thereby improving stratification and exposing potentially targetable vulnerabilities [113,250]. Emerging genomic and transcriptomic studies in FL, transformed FL, and DLBCL further illustrate how integrated profiling may reveal therapeutically relevant subgroups that are not fully captured by conventional histopathologic classification alone [251]. Molecular subtyping in DLBCL exemplifies this progress; however, its clinical implementation remains limited by variability in assay standardization, accessibility, and incomplete prospective validation [36,252]. Similarly, ctDNA and minimal residual disease (MRD) monitoring may help optimize the clinical positioning and sequencing of targeted therapies such as pirtobrutinib, brentuximab vedotin, and belinostat by enabling earlier detection of resistance or relapse, although methodological and clinical validation challenges currently restrict routine adoption [253,254].

Therapeutic resistance remains a central limitation of targeted strategies. Clonal evolution under treatment pressure frequently leads to the emergence of resistant subpopulations, as observed with covalent BTKi and mutations such as BTK C481S [255,256,257,258]. Non-covalent BTKi, including pirtobrutinib, address some of these resistance mechanisms and demonstrate activity in heavily pretreated populations; however, the durability of response and their precise positioning within treatment sequences require further clarification [259,260]. More broadly, efforts to develop pathway-driven therapies in NHL increasingly recognize that resistance is rarely mediated by a single lesion and instead reflects adaptive pathway redundancy and metabolic plasticity. This is evident in emerging preclinical work targeting convergent survival programs, including PI3Kδ- and PPARα-linked signaling in FL [261]. Combination approaches involving pirtobrutinib and agents targeting complementary pathways such as BCL2 or PI3K are biologically rational, although their clinical value must be balanced against greater toxicity, cost, and treatment complexity [262,263,264].

Combination strategies remain central to improving outcomes with the three selected agents, particularly given the redundancy and cross-talk of oncogenic signaling pathways in NHL [265,266]. Brentuximab vedotin has shown significant efficacy across CD30-positive lymphomas, especially when incorporated into combination regimens [267,268]. Nevertheless, broader application remains limited by antigen heterogeneity, uncertainty regarding optimal CD30 thresholds, and toxicity considerations, particularly in heavily pretreated or frail patients. Ongoing work continues to highlight the complexity of CD30 as a biomarker and the need for better methods to evaluate expression and predict benefit across biologically diverse NHL subtypes [269]. Studies combining brentuximab vedotin with immune checkpoint inhibitors or other immunotherapeutic approaches aim to enhance efficacy, although long-term safety, comparative benefit, and optimal sequencing remain to be established [172,270]. Similarly, belinostat offers a mechanistically distinct epigenetic strategy, but its clinical utility remains constrained by modest response rates and the absence of randomized comparative data [271,272]. Epigenetic therapies retain biologic promise, particularly in rational combinations with immunotherapy or targeted agents, yet the lack of validated predictive biomarkers remains a major barrier to broader clinical integration [273,274].

Emerging immunotherapeutic platforms may further influence the positioning of pirtobrutinib, brentuximab vedotin, and belinostat within future NHL treatment algorithms. CAR-T therapy and bispecific antibodies have demonstrated substantial activity in relapsed and refractory B-cell lymphomas [275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291]; however, their relevance to this discussion lies primarily in how they may complement, precede, or follow targeted therapies in increasingly individualized treatment sequences. Cellular and T-cell-engaging immunotherapies are already reshaping standards of care in several aggressive lymphoma settings, potentially altering the sequencing and clinical utilization of targeted small molecules and antibody–drug conjugates. In this context, ongoing studies are evaluating whether agents such as pirtobrutinib can enhance immune-based strategies or serve as bridging therapies, while brentuximab vedotin-containing regimens continue to be explored alongside immunotherapeutic combinations [172,270]. Nevertheless, despite encouraging clinical activity, the long-term positioning of pirtobrutinib, brentuximab vedotin, and belinostat within NHL treatment algorithms remains incompletely defined, particularly in the rapidly evolving era of CAR-T-cell therapy and bispecific antibodies. Important questions regarding sequencing, cumulative toxicity, resistance, comparative effectiveness, and patient selection therefore remain unresolved.

A deeper understanding of tumor evolution is essential for improving long-term disease control. Tumor plasticity enables adaptation through genetic and epigenetic mechanisms as well as through interactions with the tumor microenvironment [292]. While longitudinal monitoring with ctDNA offers potential insights into these dynamics, its integration into routine clinical decision-making remains limited by technical, analytical, and interpretive challenges [293]. Future strategies involving pirtobrutinib, brentuximab vedotin, and belinostat will likely depend on improved biomarker-driven selection, more effective resistance monitoring, and rational sequencing approaches designed to delay therapeutic escape and better integrate targeted therapies with emerging immune-based modalities.

Artificial intelligence (AI) and machine learning are also being explored as tools to refine treatment stratification and biomarker integration in NHL [294,295,296]. Although systematic review data in DLBCL suggest potential utility for predictive modeling, methodological heterogeneity and limited external validation continue to restrict clinical implementation [297]. Similarly, adaptive and biomarker-driven trial designs may facilitate more efficient evaluation of targeted combinations and sequencing strategies involving pirtobrutinib, brentuximab vedotin, and belinostat, although increasing trial complexity may also create challenges in interpretation and broader implementation [298,299].

A key objective in NHL management is the development of chemotherapy-sparing approaches that incorporate targeted therapies and immunotherapeutic combinations [300,301]. In this regard, agents such as pirtobrutinib, brentuximab vedotin, and belinostat exemplify the broader shift toward biologically driven treatment strategies, particularly for older or medically unfit patients. However, real-world tolerability, cumulative toxicity, treatment adherence, and cost-effectiveness remain important considerations [302,303]. Longer follow-up and comparative effectiveness studies are still required to clarify whether these agents can consistently replace conventional chemotherapy or are best integrated within sequential and combination-based treatment paradigms that increasingly include CAR-T-cell therapy and bispecific antibodies [304,305,306,307,308].

Finally, progress in NHL will depend not only on therapeutic innovation but also on improvements in clinical trial design and equitable access to care. Adaptive and platform-based trials are enabling more efficient evaluation of novel agents, particularly in molecularly defined populations [309,310,311]. However, disparities in access to molecular diagnostics, targeted therapies, and advanced immunotherapeutic approaches remain a major challenge [312,313,314]. The future clinical impact of pirtobrutinib, brentuximab vedotin, and belinostat will therefore depend not only on biologic efficacy, but also on improved biomarker integration, optimized sequencing strategies, comparative evaluation relative to cellular immunotherapies, and broader real-world accessibility [315].

In summary, the future role of pirtobrutinib, brentuximab vedotin, and belinostat in NHL management will likely depend on improved molecular stratification, rational combination approaches, and more precise sequencing within evolving treatment algorithms. Although emerging technologies and immunotherapeutic strategies continue to expand therapeutic possibilities, their greatest relevance lies in how they may enhance the clinical integration, resistance management, and biomarker-driven application of these three targeted agents. Future studies will therefore need to clarify the optimal integration of these therapies within increasingly complex NHL treatment frameworks that incorporate CAR-T-cell therapy, bispecific antibodies, biomarker-guided sequencing, and combination-based precision approaches. Substantial clinical and logistical challenges nevertheless remain before these precision-based strategies can be fully optimized in routine NHL care.

Table 7. Comparative characteristics of pirtobrutinib, brentuximab vedotin, and belinostat in precision therapy for non-Hodgkin lymphoma according to [33,35,36,40,107,203,316,317]. All abbreviations employed are defined in the text in the Abbreviations Section.

Agent	Therapeutic Class	Primary Molecular Target	Main NHL Indications	Biomarker Relevance	Key Resistance Mechanisms	Major Toxicities	Evidence Maturity	Potential Combination Strategies
Pirtobrutinib	Noncovalent Bruton tyrosine kinase (BTK) inhibitor	BTK within B-cell receptor (BCR) signaling pathway	Relapsed/refractory mantle cell lymphoma (MCL); other relapsed B-cell NHL subtypes under investigation	BTK pathway dependence; prior covalent BTK inhibitor exposure; B-cell molecular phenotype	BTK-independent signaling escape; PLCγ2 alterations; clonal evolution; microenvironment-mediated survival signaling	Neutropenia, fatigue, infections, diarrhea, bleeding events, atrial fibrillation (less frequent than with earlier BTK inhibitors)	Primarily early-phase and registration-supporting evidence; ongoing confirmatory studies	Venetoclax; anti-CD20 monoclonal antibodies; bispecific antibodies; CAR-T sequencing approaches
Brentuximab Vedotin	CD30-directed antibody–drug conjugate (ADC)	CD30 surface antigen linked to monomethyl auristatin E (MMAE) payload	Systemic anaplastic large-cell lymphoma (sALCL); CD30-positive peripheral T-cell lymphoma (PTCL); selected CD30-positive diffuse large B-cell lymphoma (DLBCL)	CD30 expression level and distribution; tumor microenvironment characteristics	CD30 downregulation or heterogeneity; impaired ADC internalization; drug efflux mechanisms; MMAE resistance	Peripheral neuropathy, neutropenia, fatigue, infusion-related reactions, infections	Randomized and practice-changing evidence in selected CD30-positive lymphomas	Nivolumab; chemotherapy regimens (e.g., CHP); bispecific antibodies; immune-based combinations
Belinostat	Histone deacetylase (HDAC) inhibitor	Class I and II HDAC enzymes involved in epigenetic regulation	Relapsed/refractory peripheral T-cell lymphoma (PTCL)	Epigenetic dysregulation; histone acetylation profiles; exploratory chromatin-remodeling markers	Epigenetic adaptation; compensatory survival signaling; tumor heterogeneity; limited biomarker-guided selection	Nausea, fatigue, thrombocytopenia, anemia, infections, hepatic enzyme elevation	Primarily single-arm and early-phase evidence; limited randomized confirmatory data	Hypomethylating agents; chemotherapy combinations; immunomodulatory agents; exploratory targeted combinations

provides an overview of the comparative characteristics of pirtobrutinib, brentuximab vedotin, and belinostat in precision-based therapeutic strategies for NHL;

Table 8. Contemporary management of non-Hodgkin lymphoma: clinically focused overview of current treatment strategies, including indications, representative regimens, biomarkers, toxicity considerations, and supporting evidence. All abbreviations employed are defined in the text in the Abbreviations Section.

Modality	Indication/When Used	Example Regimens/Agents	Key Evidence	Biomarkers/Toxicity
Active surveillance	Asymptomatic, low–tumor burden indolent NHL (e.g., FL)	Observation	NCCN/ESMO guidance [1,2,318]	No immediate biomarker-driven trigger; risk of delayed treatment; requires close monitoring
Radiotherapy (ISRT)	Limited-stage disease; palliation of localized symptoms	Involved-site RT	Practice guidelines [1,2,318]	Site-dependent toxicity; marrow suppression; organ-specific late effects
Front-line chemoimmunotherapy (aggressive B-cell NHL)	Newly diagnosed DLBCL and aggressive B-cell NHL	R-CHOP; pola-R-CHP	POLARIX; historical R-CHOP trials [319,320]	COO subtype, MYC/BCL2/BCL6; toxicities: cytopenias, cardiotoxicity, neuropathy
Anti-CD20–based therapy (indolent NHL)	First-line or relapsed follicular and CD20 + NHL	Rituximab monotherapy; BR; rituximab-chemotherapy followed by maintenance in selected cases	StiL; BRIGHT [321,322]	CD20 expression; infections, hypogammaglobulinemia, HBV reactivation
BTKi (MCL)	Relapsed/refractory MCL	Pirtobrutinib	BRUIN study [33]	MCL subtype; bleeding, infections, atrial arrhythmias (class effect)
Immunomodulatory combinations	Transplant-ineligible relapsed/refractory DLBCL	Tafasitamab + lenalidomide	L-MIND [323]	CD19 expression; neutropenia, infections, thromboembolism
Bispecific antibodies	Relapsed/refractory B-cell NHL (DLBCL, FL)	Epcoritamab; glofitamab; mosunetuzumab	EPCORE NHL-1; NP30179; GO29781 [324,325,326]	CD20 expression; CRS, ICANS, cytopenias
ADCs	Front-line (selected) or relapsed NHL; CD30+ PTCL	Polatuzumab vedotin; brentuximab vedotin; brentuximab vedotin + lenalidomide + rituximab in relapsed/refractory LBCL	POLARIX; ECHELON-2 [36,319]	CD79b (pola), CD30 (BV); neuropathy, cytopenias
Epigenetic therapy (HDAC inhibitors)	Relapsed/refractory PTCL	Belinostat	BELIEF trial [40]	No routine biomarker; myelosuppression, fatigue, hepatotoxicity
CAR-T cell therapy	Relapsed/refractory LBCL; early relapse or refractory disease	Axi-cel; liso-cel; other approved CD19 CAR-T products by subtype/line	ZUMA-1; TRANSCEND [327,328]	CD19 expression; CRS, ICANS, prolonged cytopenias
Stem-cell transplantation	Selected relapsed/refractory aggressive NHL or PTCL	Auto-HSCT; allo-HSCT in selected cases	Historical transplant data [1,2,318]	Fitness, disease status; TRM, GVHD (allo), infections

outlines contemporary NHL management, including indications, treatment regimens, biomarkers, toxicity profiles, and levels of supporting evidence; while Figure 5 illustrates therapeutic pathways and treatment algorithms integrating biomarker-driven selection and treatment sequencing in NHL.

6. Conclusions

NHL represents a biologically heterogeneous group of malignancies in which precision oncology is increasingly reshaping therapeutic decision-making by aligning treatment strategies with disease biology. The clinical development of pirtobrutinib, brentuximab vedotin, and belinostat illustrates three complementary therapeutic paradigms—targeting intracellular signaling, delivering selective cytotoxic payloads, and modulating epigenetic regulation—highlighting the ability to intervene at multiple levels of lymphomagenesis.

Collectively, these agents also demonstrate that therapeutic efficacy depends not only on target expression, but also on broader biologic context, including molecular subtype, tumor microenvironment, prior treatment exposure, and mechanisms of adaptive resistance. The experience with pirtobrutinib highlights the importance of overcoming acquired resistance associated with covalent BTK inhibition, particularly BTK C481 alterations, while also illustrating the growing relevance of treatment sequencing in heavily pretreated B-cell NHL. Brentuximab vedotin emphasizes both the therapeutic value and the limitations of biomarker-directed ADC therapy, as CD30 expression alone does not fully predict clinical benefit and must be interpreted within a broader biologic framework. In contrast, belinostat illustrates the challenges associated with epigenetic therapies in PTCL, where biologic rationale and regulatory approval have preceded the development of robust predictive biomarkers and randomized comparative evidence.

These agents further underscore the importance of balancing efficacy with toxicity and long-term treatment feasibility. Peripheral neuropathy associated with brentuximab vedotin, class-specific toxicities linked to BTK inhibition, and the hematologic and systemic adverse effects observed with HDAC inhibition all influence treatment selection, sequencing, and combination strategies in clinical practice. At the same time, differences in evidence maturity across these therapies remain highly relevant. While agents such as brentuximab vedotin are supported by randomized phase III data in selected NHL settings, belinostat continues to rely primarily on single-arm phase II evidence, highlighting the uneven pace at which targeted therapies advance from biologic promise to fully validated standards of care.

Importantly, the evolving therapeutic landscape of NHL increasingly requires adaptable and biomarker-informed strategies capable of responding to clonal evolution and therapeutic resistance. The integration of molecular profiling, rational combination approaches, and improved resistance monitoring may help optimize the positioning of these agents within future treatment algorithms. However, substantial challenges remain regarding biomarker validation, comparative effectiveness, sequencing after novel immunotherapies, cumulative toxicity, and equitable access to advanced therapies.

Overall, pirtobrutinib, brentuximab vedotin, and belinostat together illustrate both the progress and the ongoing limitations of precision oncology in NHL. Their development highlights critical lessons regarding biomarker selection, resistance mechanisms, toxicity management, and the necessity of aligning therapeutic intensity and sequencing with disease biology and patient-specific factors. Continued efforts to refine molecular stratification, validate predictive biomarkers, and generate higher-level comparative evidence will be essential to more fully integrate targeted therapies into coherent, biologically informed NHL treatment frameworks.