Beyond Chemoimmunotherapy: Emerging Cellular and Targeted Therapies in Transformed Follicular Lymphoma: A Scoping Review

Abstract

Introduction

Transformed follicular lymphoma (t-FL) is an aggressive lymphoma with limited prospective evidence to guide treatment, particularly in the relapsed setting. We summarized the current evidence on emerging cellular and targeted therapies that extend beyond conventional chemoimmunotherapy.

Methods

This scoping review was conducted in accordance with the PRISMA extension for Scoping Reviews (PRISMA-ScR) and structured using the Population–Concept–Context (PCC) framework. Adults with histologically confirmed or strongly suspected t-FL were the population of interest. Findings were synthesized narratively.

Results

Seventeen studies met inclusion criteria across three therapeutic categories: CAR-T therapy (7 interventional trials, n = 130 t-FL patients in reported subsets), CD20×CD3 bispecific antibodies (BsAbs; n = 61 t-FL patients with extractable outcomes), and selinexor (n = 31 t-FL patients); together encompassing approximately 222 t-FL patients across primary interventional cohorts with extractable outcomes. CAR-T products achieved overall response rates (ORR) of 52–83% and complete response (CR) rates of 40–58%; randomized second-line trials favored axicabtagene ciloleucel and lisocabtagene maraleucel over standard care. In real-world CAR-T series, ORR ranged from 82–92% and CR rates from 64–67% across registry cohorts. BsAbs were active in heavily pretreated disease (epcoritamab ORR 50%/CR 44%; glofitamab ORR 55%/CR 35%), with predominantly low-grade cytokine release syndrome. Selinexor showed more modest efficacy (ORR 39%/CR 16%) but durable benefit in complete responders.

Conclusions

Current evidence supports a stepwise treatment framework: DLBCL-like induction at transformation, autologous stem-cell transplant in fit, chemosensitive responders, CAR-T as the preferred option at first relapse, BsAbs after CAR-T or when cellular therapy is not feasible, and selinexor in later-lines of therapy. Additional prospective t-FL–inclusive trials are needed to refine treatment selection and biomarker-guided sequencing.

Graphical Abstract

Keywords

transformed follicular lymphoma histologic transformation scoping review CAR T-cell therapy bispecific antibodies selinexor

Introduction

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma and the most common indolent subtype.¹ Although untreated patients typically survive for years, the natural history of FL can be dramatically altered by histologic transformation (HT) into a more aggressive lymphoma. The spectrum of indolent lymphomas susceptible to transformation includes FL, marginal zone lymphoma, lymphoplasmacytic lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma.²

Among these, FL transformation has been the most extensively characterized, occurring at a consistent rate of 1–2% per year.² Transformation typically presents with rapid lymphadenopathy, extranodal disease, B symptoms, elevated lactate dehydrogenase (LDH), and occasional hypercalcemia.² Although historical outcomes were poor, contemporary management has improved survival, particularly when transformation occurs in patients with limited prior therapy.^3-5

Despite these advances, prospective evidence specifically addressing transformed disease remains scarce. Most current treatment standards are extrapolated from subset analyses of trials in aggressive lymphoma, and several pivotal registration programs explicitly excluded transformed histology. This scoping review summarizes the available evidence on the diagnosis and management of t-FL, with a focus on emerging cellular and targeted therapies, and proposes an evidence-informed management algorithm to support clinical decision-making and identify research priorities.

Methods

Protocol and Registration

This scoping review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist (Tricco et al, 2018), and the methodology of Arksey and O'Malley as refined by the Joanna Briggs Institute. The completed PRISMA-ScR checklist is provided as a supplementary file. A formal protocol was developed a priori and is available from the corresponding author on request. The review was not pre-registered; however, all eligibility criteria, search strategy elements, and data-charting variables were defined before screening.

Review Questions and PCC Framework

The review was structured around the Population–Concept–Context (PCC) framework. The Population comprised adults (≥18 years) with FL and histologically confirmed or strongly suspected histologic transformation. The Concept covered diagnostic strategies and therapeutic approaches, including chemoimmunotherapy, autologous and allogeneic stem-cell transplantation, CD19-directed CAR-T therapy, CD20×CD3 bispecific antibodies, and novel targeted agents (e.g., selinexor), with reported efficacy and safety outcomes. The Context included all care settings (clinical-trial and real-world) and all geographic regions, incorporating peer-reviewed studies and major hematology meeting abstracts with extractable t-FL data.

Eligibility Criteria

Eligible study designs were interventional trials and trial expansions (CAR-T, CD20×CD3 bispecific antibodies, selinexor); registries; and phase II/III randomized studies. Studies were required to report at least one efficacy endpoint — overall response rate (ORR), complete response (CR), duration of response (DOR), progression-free survival (PFS), event-free survival (EFS), or overall survival (OS) and/or safety outcomes including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or grade ≥3 adverse events.

Reports published from 1 January 2000 through 31 May 2025, in any language, were considered. For mixed-histology datasets, inclusion required either explicit identification of a t-FL subset or sufficient detail to abstract t-FL–specific results. Single case reports, narrative editorials, and letters without primary data were excluded, as were studies with fewer than ten patients when no t-FL subgroup outcomes could be extracted, reports without separable t-FL data, pediatric-only studies, and purely diagnostic or radiologic reports.

Information Sources and Search Strategy

A systematic search was performed in three electronic databases: PubMed/MEDLINE, EMBASE, and the Cochrane Library. This was supplemented by manual screening of conference proceedings from the American Society of Hematology (ASH) and the European Hematology Association (EHA) from 2020 to 2025, as well as hand-searching the reference lists of recent narrative reviews.

The search strategy combined controlled vocabulary terms, including MeSH and Emtree, with free-text terms grouped under three core concepts and linked using Boolean operators: (i) “transformed follicular lymphoma” OR “histologic transformation” OR “Richter-like transformation”; AND (ii) “CAR-T″ OR “chimeric antigen receptor” OR “axicabtagene” OR “lisocabtagene” OR “tisagenlecleucel” OR “bispecific antibody” OR “epcoritamab” OR “glofitamab” OR “mosunetuzumab” OR “selinexor” OR “XPO1” OR “autologous stem cell transplant”; AND (iii) “efficacy” OR “response” OR “survival” OR “safety”.

Study Selection and Data Management

All retrieved citations were imported into EndNote 21 and de-duplicated. Reasons for full-text exclusion were recorded and are summarized in the PRISMA-ScR flow diagram (Figure 1).

Figure 1.

PRISMA-ScR flow diagram of the study selection process

Data Extraction

Extracted data items included bibliographic information, including first author, year, and country; study design and setting; sample size of patients with transformed follicular lymphoma; intervention and treatment line; key efficacy endpoints, including overall response rate (ORR), complete response (CR), duration of response (DOR), progression-free survival (PFS), event-free survival (EFS), and overall survival (OS); and safety outcomes, including cytokine release syndrome (CRS) grade, immune effector cell-associated neurotoxicity syndrome (ICANS), grade ≥3 adverse events, and treatment-related mortality.

Evidence Synthesis and Risk-Of-Bias Assessment

Consistent with PRISMA-ScR guidance, no formal risk-of-bias assessment was performed, as the aim was to map the breadth and nature of available evidence rather than to generate pooled comparative estimates. Quantitative meta-analysis was not performed because of marked clinical and methodological heterogeneity. Limitations of the underlying evidence base, including selection bias, small t-FL subgroups, and heterogeneous transformation definitions, are discussed in the limitations section.

Results

Selection of Sources of Evidence

The database search retrieved 680 records, supplemented by 45 records from conference proceedings and reference screening. After removal of 276 duplicates, 449 records were screened by title and abstract; 89 full texts were assessed for eligibility, and 17 studies fulfilled the inclusion criteria (Figure 1). The most frequent reason for full-text exclusion was lack of extractable t-FL data (n = 45).

Characteristics of Included Studies

Of the 17 included studies, the primary interventional cohorts reported extractable t-FL data across three therapeutic categories: CAR-T (7 trials; n = 130 t-FL patients in reported subsets), CD20×CD3 bispecific antibodies (3 studies; n = 61 t-FL patients with extractable outcomes), and selinexor (1 study; n = 31 t-FL patients), totaling approximately 222 t-FL patients with extractable outcomes. t-FL proportions across the CAR-T trials ranged from 5–22% per treatment arm. The remaining studies provided observational, real-world, or supportive evidence informing the role of chemoimmunotherapy and ASCT. Synthesized findings are summarized in evidence tables (Tables 1-5), in a practical-positioning matrix (Table 6), and in the proposed management algorithm (Figure 2). The ORR and CR rates across included studies, stratified by therapeutic class, are summarized in Figure 3, while key safety signals across treatment modalities are shown in Figure 4.

Table 1.

Observational and Chemoimmunotherapy Studies in Transformed Follicular Lymphoma

Study	Population	Treatment approach	Key outcomes	Notes
Retrospective cohort⁶	60 biopsy-proven t-FL	R-CHOP in 59% (others varied)	Median OS 50 mo; 5-yr OS 66%	DLBCL-type salvage patterns
National LymphoCare Study (NLCS)⁷	379 t-FL (147 biopsy; 232 clinical)	Rituximab mono 26%; rituximab-based CIT 35%	Biopsy-proven: median PFS 12 mo; Overall OS 60 mo	Prospective registry
PRIMA post-hoc analysis⁸	Treatment-naïve FL who later transformed	DLBCL-type salvage chemoimmunotherapy	5-yr OS post-transformation ∼48–50%	Post-hoc; first-line CIT responders

DLBCL, diffuse large B-cell lymphoma; OS, overall survival; PFS, progression-free survival; t-FL, transformed follicular lymphoma; R-CHOP, rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone.

Table 2.

CD19-Directed CAR-T Interventional Trials in Transformed Follicular Lymphoma

Study	Setting/Line	t-FL cases	Intervention	Efficacy	Key outcomes/Notes
ZUMA-1⁹	R/R LBCL incl. t-FL (≥3L)	n = 16 (67% of tFL cohort 2)	Axicabtagene ciloleucel (axi-cel)	ORR 83%, CR 58%; median PFS 5.9 mo; median OS 25.8 mo	Durable responses; CD19-neg. relapses reported
TRANSCEND NHL-001¹⁰	R/R LBCL incl. t-FL (≥3L)	n = 60 (22%; N = 270)	Lisocabtagene maraleucel (liso-cel)	ORR 73%, CR 53%; median PFS 6.8 mo; median OS 27.3 mo	Active in high-risk subtypes
PILOT¹¹	ASCT-ineligible 2L DLBCL	n = 9 (15%; N = 61 infused)	Lisocabtagene maraleucel	ORR 80%, CR 54%; median PFS 9.0 mo; median OS NR	Durable CRs in frail/ASCT-ineligible
JULIET¹²	R/R DLBCL incl. t-FL (≥3L)	n = 21 (18%; N = 115 infused)	Tisagenlecleucel (tisa-cel)	ORR 52%, CR 40%; median PFS 2.9 mo; median OS 11.1 mo	Lower durability vs other CAR-T products
ZUMA-7¹³	2L randomized vs SOC	n = 19 (11%) axi-cel arm; n = 27 (15%) SOC arm	Axicabtagene ciloleucel	CR 65% vs 32%; EFS 8.3 vs 2.0 mo; PFS 14.7 vs 3.7 mo; OS NR vs 31 mo (axi-cel vs SOC)	EFS 8.3 vs 2.0 mo; positive RCT
TRANSFORM¹⁴	2L randomized vs SOC	n = 5 (5.4%) liso-cel arm; n = 6 (6.5%) SOC arm	Lisocabtagene maraleucel	CR 74% vs 43%; PFS NR vs 6.2 mo; OS NR vs 29.9 mo (liso-cel vs SOC)	Positive randomized 2L trial
BELINDA¹⁵	2L randomized vs SOC	Included; t-FL not separately reported in primary publication	Tisagenlecleucel	No superiority vs SOC	Negative 2L RCT

ASCT, autologous stem-cell transplant; CR, complete response; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; LBCL, large B-cell lymphoma; ORR, overall response rate; PFS, progression-free survival; PMBCL, primary mediastinal B-cell lymphoma; R/R, relapsed/refractory; SOC, standard of care; t-FL, transformed follicular lymphoma; ≥3L, third line or later.

Table 3.

CD20×CD3 Bispecific Antibody Trials in Transformed Follicular Lymphoma

Study	Agent	Setting	t-FL Cases	Efficacy (t-FL)	Durability/Safety
EPCORE NHL-1¹⁶	Epcoritamab	R/R LBCL; post-CAR-T allowed	n = 32	ORR 50%, CR 44%	Median DOR NR; 36-mo response 55%; CRS grade 1–2 predominant; ICANS ∼6%
NP30179 (Phase I/II)¹⁷	Glofitamab	R/R LBCL	n = 29	ORR 55.2%, CR 34.5%	Median DOR 5.5 mo; PFS plateau ∼24% at 8 mo; low-grade CRS common
STARGLO/OLYMPIA-5^18,19	Odronextamab/Glofitamab	Pivotal programs	Excluded	—	Exclusion limits generalizability to t-FL

CAR-T, chimeric antigen receptor T-cell therapy; CR, complete response; CRS, cytokine release syndrome; DOR, duration of response; FL, follicular lymphoma; ICANS, immune effector cell-associated neurotoxicity syndrome; LBCL, large B-cell lymphoma; NR, not reached; ORR, overall response rate; PFS, progression-free survival; R/R, relapsed/refractory; t-FL, transformed follicular lymphoma.

Table 4.

Selinexor as a Targeted Agent in Transformed Follicular Lymphoma

Study	Agent	Population	Efficacy (t-FL Subgroup)	Regulatory/Guidance
SADAL (Phase 2b)²⁰	Selinexor (XPO1 inhibitor)	R/R DLBCL incl. Transformed indolent; t-FL n = 31 (∼24%)	ORR 38.7%, CR 16.1%; Median DOR 23.2 mo (CRs); Median OS 9.1 mo overall	FDA accelerated approval 2020; NCCN 2025 Cat 2A (t-FL after ≥2 lines)

CR, complete response; DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; FDA, U.S. Food and Drug Administration; NCCN, National Comprehensive Cancer Network; NR, not reached; ORR, overall response rate; OS, overall survival; R/R, relapsed/refractory; t-FL, transformed follicular lymphoma; XPO1, exportin-1.

Table 5.

Real-World, Case-Based, and Preclinical Evidence in Transformed Follicular Lymphoma

Study	Population	Intervention	Outcomes	Notes
Real-world CD19 CAR-T (China)²¹	14 t-FL incl. blastoid variant	CD19 CAR-T	ORR 92%; 2-yr PFS 67%, OS 73%	Small single-center series
US registry/ASH abstract²²	t-FL vs de novo DLBCL (real-world)	CD19 CAR-T	Improved OS/PFS vs historical	Abstract-level evidence
Case: CAR-T + ASCT²³	TP53-mut. bulky CD20-neg. t-FL	CD19 CAR-T then ASCT	Complete metabolic remission at 1 mo	Single case
Case: CD20/CD30 Bispecific CAR-T²⁴	Bulky CD19-neg. t-FL	CD20/CD30 bispecific CAR-T	12+ mo remission; no CRS/ICANS	Single case
Preclinical: CD19/CD22 dual CAR-T²⁵	FL/t-FL models (CD19-loss)	CD19/CD22 dual CAR-T	Preclinical efficacy; escape mitigation	Laboratory study
LOTIS-2²⁶	n = 29 (20%) transformed indolent lymphoma; t-FL not separately reported	Loncastuximab tesirine (ADC)	Overall cohort: ORR 48%, CR 25%; PFS 4.9 mo; OS 9.5 mo (t-FL not separately analyzed)	ADC class; Parry & Okosun (Blood 2025) Table 2; t-FL not separately analyzed

ASCT, autologous stem-cell transplant; CAR-T, chimeric antigen receptor T-cell therapy; CRS, cytokine release syndrome; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; ICANS, immune effector cell-associated neurotoxicity syndrome; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; t-FL, transformed follicular lymphoma.

Table 6.

Practical Positioning of Available Therapies in Transformed Follicular Lymphoma

Therapy/Approach	Typical Clinical Setting	Main Strengths	Main Limitations	Practical Role in Current Care
R-CHOP–based chemoimmunotherapy	Newly transformed, anthracycline-naïve t-FL	Widely available; familiar DLBCL backbone; supported by historical cohorts	Suboptimal in high-risk disease; limited prospective t-FL data	Standard first-line approach for most newly transformed cases
Dose-adjusted R-EPOCH	High-grade/double-hit biology (MYC+BCL2)	More intensive option for adverse biology	Greater toxicity; t-FL evidence remains extrapolative	Consider in selected high-grade/double-hit cases
Autologous stem-cell transplant (ASCT)	Fit, chemosensitive patients; PET-negative remission	Can prolong remission; durable disease control in selected patients	Retrospective evidence; uncertain OS advantage; transplant toxicity	Consolidation in selected PET-responsive, fit patients
CD19-directed CAR-T therapy	R/R t-FL; first relapse in eligible patients	Strongest evidence base; deep, durable remissions; FDA-approved	Access; manufacturing time; CRS/ICANS; CD19-neg. relapse	Preferred option at first relapse for eligible patients
CD20×CD3 bispecific antibodies	Post-CAR-T relapse or CAR-T-ineligible patients	Off-the-shelf access; meaningful activity; manageable toxicity	Limited t-FL-specific data; pivotal trials often excluded t-FL	Key later-line option; alternative when CAR-T not feasible
Selinexor	Later-line R/R disease; frail/non-cellular therapy candidates	Oral; distinct mechanism; FDA-labelled for t-FL	More modest efficacy; nausea, fatigue, thrombocytopenia	Later-line option when cellular/bispecific therapy unsuitable

ASCT, autologous stem-cell transplant; BR, bendamustine-rituximab; CAR-T, chimeric antigen receptor T-cell therapy; CRS, cytokine release syndrome; DLBCL, diffuse large B-cell lymphoma; ICANS, immune effector cell-associated neurotoxicity syndrome; OS, overall survival; R-CHOP, rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone; R-EPOCH, rituximab-etoposide-prednisone-vincristine-cyclophosphamide-doxorubicin; t-FL, transformed follicular lymphoma.

Figure 2.

Evidence-informed management algorithm for transformed follicular lymphoma. ASCT, autologous stem-cell transplant; BR, bendamustine-rituximab; CAR-T, chimeric antigen receptor T-cell therapy; CR, complete response; ORR, overall response rate; POD24, progression of disease within 24 months

Figure 3.

Overall response rate (ORR) and complete response (CR) rate across included studies in transformed follicular lymphoma, stratified by therapeutic class

Figure 4.

Key safety signals across therapy classes in transformed follicular lymphoma. Rates are approximate estimates from pivotal trial safety tables and represent the overall trial population (t-FL subgroups were too small for separate safety reporting in most trials). CRS = cytokine release syndrome; ICANS = immune effector cell-associated neurotoxicity syndrome

Notably, five pivotal registration programs (ZUMA-5, ELARA, TRANSCEND FL, STARGLO, OLYMPIA-5) excluded transformed histology, despite broader approvals in DLBCL settings.^18,27-29 This persistent exclusion underscores the need for dedicated, t-FL–specific prospective studies to refine treatment selection and sequencing.

CAR-T Therapy in t-FL

Seven interventional CAR-T trials with extractable t-FL subgroup data (total n = 130 t-FL patients across reported subsets; Parry and Okosun, Blood 2025) informed the CAR-T evidence base (Table 2). In TRANSCEND NHL-001, 60 patients with t-FL (22% of 270 treated) received lisocabtagene maraleucel and achieved ORR 73%/CR 53% with a median PFS of 6.8 months.¹⁰ ZUMA-1 included a t-FL subset treated with axicabtagene ciloleucel (ORR 83%/CR 58%, with sustained CR rates).⁹ JULIET (tisagenlecleucel) showed lower durability in t-FL relative to other products.¹² Among randomized second-line trials, ZUMA-7 (axi-cel) and TRANSFORM (liso-cel) demonstrated superiority over standard chemo-transplant strategies (CR 65% vs 32% and 74% vs 43%, respectively), whereas BELINDA (tisa-cel) did not.^13-15 Real-world data corroborate meaningful activity. In the TRANSCAR registry, 60 patients with transformed indolent NHL treated with CAR-T achieved ORR 82% and CR 64%, with superior outcomes compared to de novo LBCL.²² A complementary US multicenter analysis of 691 patients (139 t-FL, 20%) similarly demonstrated improved PFS and OS for t-FL versus de novo DLBCL following CAR-T therapy.²²

CD20×CD3 bispecific Antibodies

Two BsAb studies provided extractable t-FL outcomes (epcoritamab and glofitamab; n = 61 t-FL patients). A third study of mosunetuzumab enrolled 23 t-FL patients within an 88-patient DLBCL/t-FL cohort, but did not report t-FL outcomes separately, precluding efficacy extraction.^26,30 BsAb activity in heavily pretreated disease (Table 3). In EPCORE NHL-1, 32 patients with t-FL achieved ORR 50%/CR 44%, with 55% responses ongoing at 36 months.¹⁶ NP30179 (glofitamab) reported ORR 55.2%/CR 34.5% with median DOR of 5.5 months in 29 t-FL patients.¹⁷ Cytokine release syndrome was predominantly low grade and manageable with step-up dosing and corticosteroid prophylaxis.

Selinexor

Selinexor remains the only non-cellular agent with FDA labeling that explicitly includes t-FL (Table 4). The pivotal SADAL phase 2b study enrolled 31 patients with t-FL (24% of 134) and reported ORR 38.7%/CR 16.1%, numerically higher than the de novo DLBCL subgroup (ORR 26.2%).²⁰ Among complete responders, the median DOR was 23.2 months, and median OS in the t-FL subgroup was 9.1 months.³¹

Real-World, Case-Based, and Preclinical Evidence

Six additional reports provided supportive evidence, including real-world CAR-T cohorts, an antibody-drug conjugate study with a t-FL subgroup (LOTIS-2), single-patient experiences with bispecific or sequential CAR-T strategies, and a preclinical CD19/CD22 dual-targeting program addressing CD19-loss escape (Table 5).

Summary of Findings

Biology and Pathogenesis

Transformation of FL is associated with retained lineage but higher-grade biology. Most cases remain germinal-center B-cell type, with a smaller subset shifting to activated B-cell phenotype. MYC deregulation is a key event and, when combined with BCL2 rearrangement, defines double-hit biology associated with inferior outcomes.^32,33 Cooperating lesions in cell-cycle regulation, DNA-damage response, immune escape, and survival signaling are common. ABC patterns frequently involve MYD88, CD79B, and BCL10, whereas GCB patterns more often show REL amplification and TP53/CDKN2A/B abnormalities.^32,34-36 Multi-omic studies confirm clonal relatedness between t-FL and antecedent FL through shared t(14;18) breakpoints and aberrant somatic hypermutation patterns.^32,37 Whole-genome analyses describe biologically distinct FL subtypes, including DLBCL-like FL with greater transformation risk, and microenvironmental remodeling marked by reduced T follicular helper cells and increased exhausted T-cell populations.^38-46 Collectively, these data support PET-directed re-biopsy of the highest-SUV lesion and molecular evaluation at transformation, including MYC/BCL2/BCL6 testing.⁴⁷

Epidemiology and Clinical Presentation

Approximately 10–15% of patients with FL experience HT during the disease course, at an annual rate of 1–2% across multiple cohorts, though contemporary rituximab-era registries suggest a lower cumulative rate of 4–13% at 10 years.^6,7,48 Two large cohorts illustrate this risk and the value of biopsy⁴⁹: a prospective study of >600 newly diagnosed FL patients reported HT in 11% over a median of 5 years, with biopsy confirmation in 85%⁶; in the PRIMA trial, 21% of 194 patients with biopsy-proven relapse showed transformation, and transformation was associated with markedly shorter time to recurrence (9.6 vs 22.8 months).⁸ Established baseline risk factors include multiple extranodal sites, ECOG performance status >1, elevated LDH, B symptoms, advanced stage, low albumin, high FLIPI/IPI, failure to achieve CR after first-line therapy, and POD24.⁴ Treatment exposure may also influence transformation risk, with population-based data suggesting higher t-FL rates after rituximab–bendamustine than after R-CVP.⁴² Early transformation (<18 months) is associated with substantially worse 5-year survival than later events.^6,50 Clinically, HT should be suspected with rapid nodal growth, focal SUV >10, unexpected extranodal involvement, early treatment failure, B symptoms, or hypercalcemia; biopsy remains the diagnostic gold standard despite documented underuse.^42,51-53

Current and Emerging Treatment Strategies

Treatment of t-FL at transformation remains anchored in DLBCL-directed chemoimmunotherapy. R-CHOP is the standard for most anthracycline-naïve patients,^7,8,48 whereas dose-adjusted R-EPOCH is reserved for high-grade biology with MYC and BCL2 rearrangements.^54-56 Non-anthracycline rituximab-based regimens (BR or polatuzumab-based combinations) are options when anthracyclines are contraindicated.⁵⁷ ASCT remains a selective option in fit, chemosensitive responders, with the strongest signal for durable disease control in PET-negative remission^58-61; randomized t-FL–specific evidence is lacking, and treatment-related morbidity must be balanced against potential benefit (Table 1).

Among emerging therapies, CD19-directed CAR-T currently has the strongest evidence base in relapsed/refractory t-FL (Table 2) and is the preferred option at first relapse for eligible patients. Confirmation of CD19 expression is essential, and CD19-negative relapse is an established mechanism of post-CAR-T resistance. 1110, 12 and 62 CD20×CD3 bispecific antibodies (Table 3) provide an off-the-shelf alternative after CAR-T failure or when CAR-T is not feasible because of age, comorbidity, logistics, or access.^17,26,30,63 Their toxicity profile is generally manageable and is dominated by low-grade CRS.^17,63 Selinexor (Table 4) remains a useful later-line option, particularly for frail or heavily pretreated patients, and is the principal targeted agent with regulatory inclusion of t-FL.^20,31

Practical Positioning and Proposed Algorithm

The practical positioning of available modalities is summarized in Table 6, and an evidence-informed management algorithm is presented in Figure 2. In brief, transformation should be biopsy-confirmed whenever feasible (PET-CT-guided when possible)^64,65; first-line treatment follows a DLBCL-like strategy tailored to disease biology and prior anthracycline exposure; ASCT is offered to fit, chemosensitive responders⁶¹; CAR-T is prioritized at first relapse in eligible patients; and bispecific antibodies and selinexor are reserved for later lines or CAR-T-ineligible settings.

Limitations

This scoping review is descriptive by design and was intended to map the available evidence rather than generate pooled comparative estimates; accordingly, no formal risk-of-bias assessment or meta-analysis was performed, consistent with PRISMA-ScR guidance. Several limitations in the underlying literature should be acknowledged. First, many pivotal trials excluded transformed histology or reported only small t-FL subgroups, creating underrepresentation and potential selection bias. Second, definitions of transformation and diagnostic methods varied across studies, including biopsy-proven and clinically suspected cases.^5,7 Third, heterogeneity in prior therapy, anthracycline exposure, timing of transformation, and biomarker characterization (e.g., double-hit status, TP53 alterations, cell of origin) limits external validity. Fourth, real-world datasets often lack centralized pathology review, standardized response assessment, and complete follow-up, with possible overlap between cohorts. Finally, several findings derived from subgroup analyses, post-hoc reports, or conference abstracts with immature follow-up, increasing the risk of selective reporting. Few studies directly address optimal sequencing, including CAR-T versus early bispecific use, or the management of CD19-negative relapse.

Conclusion

Although the evidence base for transformed follicular lymphoma remains limited, the current literature supports a coherent treatment framework. Biopsy confirmation should be pursued whenever feasible, and initial management should follow a DLBCL-like approach tailored to disease biology and patient fitness. ASCT remains an option for selected chemosensitive patients, while CAR-T is the preferred strategy at first relapse in eligible patients. Bispecific antibodies provide an important option after CAR-T failure or when cellular therapy is not feasible, and selinexor is best reserved for later-line or oral-therapy settings. Across these therapies, careful toxicity management and infection prophylaxis remain essential. Future progress will depend on prospective, t-FL–inclusive trials and biomarker-guided sequencing studies.

Supplemental Material

Supplemental Material - Beyond Chemoimmunotherapy: Emerging Cellular and Targeted Therapies in Transformed Follicular Lymphoma: A Scoping Review

Supplemental Material for Beyond Chemoimmunotherapy: Emerging Cellular and Targeted Therapies in Transformed Follicular Lymphoma: A Scoping Review by Abdulrahman F. Al-Mashdali, Rola Ghasoub, Shrouq Hwafdeh, and Mohamed A. Yassin in Cancer Control.

Footnotes

Acknowledgements

The authors acknowledge Qatar Foundation for covering the open-access publication fees upon acceptance. The authors used OpenAI solely for language polishing, graphical abstract/figures creation, and refinement during manuscript preparation; all content was subsequently reviewed and edited by the authors, who take full responsibility for the final manuscript.

ORCID iD

Abdulrahman F. Al-Mashdali

Ethical Considerations

This study is a review of previously published literature and did not involve human participants, human tissue, or animal experiments conducted by the authors.

Consent to Participate

This study did not involve direct patient participation or the collection of identifiable individual data.

Author Contributions

Abdulrahman F. Al-Mashdali and Rola Ghasoub contributed equally to this work and share first authorship. A.F.A. and R.G. contributed to conceptualization, methodology, investigation, formal analysis, and drafting of the original manuscript. Shrouq Hwafdeh contributed to investigation and data curation. Mohamed A. Yassin contributed to resources, critical revision, and supervision. All authors reviewed, edited, and approved the final manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Open-access publication fees for this manuscript will be covered by Qatar Foundation upon acceptance.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

No new datasets were generated or analyzed in this study. All data supporting the findings of this review are available within the article and the cited references.*

Supplemental Material

Supplemental material for this article is available online.

References

Alaggio

Amador

Anagnostopoulos

, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022;36:1720-1748.

Smith

. Transformed lymphoma: what should I do now? Hematology Am Soc Hematol Educ Program. 2020;2020:306-311.

Alderuccio

Lossos

Rodrigues

, et al. Utilizing clinical transformation criteria for prognostic stratification in follicular lymphoma prior to initial immunochemotherapy. Hematol Rep. 2024;16(4):757-768.

Zheng

Liu

Guan

Wang

. Outcomes of the transformation of follicular lymphoma to diffuse large B-cell lymphoma in the rituximab era: a population-based study. Cancer Med. 2024;13:e7120.

Florindez

Chihara

Reis

Lossos

Alderuccio

. Risk of transformation by frontline management in follicular and marginal zone lymphomas: a US population-based analysis. Blood Adv. 2024;8:4423-4432.

Link

Maurer

Nowakowski

, et al. Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource. J Clin Oncol. 2013;31:3272-3278.

Wagner-Johnston

Link

Byrtek

, et al. Outcomes of transformed follicular lymphoma in the modern era: a report from the National LymphoCare Study (NLCS). Blood. 2015;126:851-857.

Sarkozy

Trneny

Xerri

, et al. Risk factors and outcomes for patients with follicular lymphoma who had histologic transformation after response to first-line immunochemotherapy in the PRIMA trial. J Clin Oncol. 2016;34:2575-2582.

Neelapu

Jacobson

Ghobadi

, et al. Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood. 2023;141:2307-2315.

10.

Abramson

Palomba

Gordon

, et al. Two-year follow-up of lisocabtagene maraleucel in relapsed or refractory large B-cell lymphoma in TRANSCEND NHL 001. Blood. 2024;143:404-416.

11.

Sehgal

Hoda

Riedell

, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23:1066-1077.

12.

Schuster

Bishop

Tam

, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56.

13.

Locke

Miklos

Jacobson

, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654.

14.

Kamdar

Solomon

Arnason

, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308.

15.

Bishop

Dickinson

Purtill

, et al. Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N Engl J Med. 2022;386:629-639.

16.

Vose

Cheah

Clausen

, et al. 3-year update from the EPCORE NHL-1 trial: epcoritamab leads to deep and durable responses in relapsed or refractory large B-cell lymphoma. Blood. 2024;144:4480.

17.

Dickinson

Carlo-Stella

Morschhauser

, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387:2220-2231. [t-FL subgroup outcomes reported in supplementary data of NP30179 phase I/II study].

18.

Vitolo

Phillips

Alonso

, et al. PB2266: TRIAL IN PROGRESS: phase 3 trial of odronextamab plus lenalidomide versus rituximab plus lenalidomide in relapsed/refractory follicular lymphoma and marginal zone lymphoma (OLYMPIA-5). Hemasphere. 2023;7:e49668c2.

19.

Abramson

Hertzberg

, et al. Glofitamab plus gemcitabine and oxaliplatin (GemOx) versus rituximab-GemOx for relapsed or refractory diffuse large B-cell lymphoma (STARGLO): a global phase 3, randomised, open-label trial. Lancet. 2024;404:1940-1954.

20.

Kalakonda

Maerevoet

Cavallo

, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7:e511-e522.

21.

Stephan

Di Blasi

Roulin

, et al. TRANSCAR: real-world outcomes of CD19 CAR T-cell therapy in relapsed/refractory transformed indolent lymphomas. Blood Adv. 2025;9:4693-4704.

22.

Thiruvengadam

Merryman

Wang

, et al. Outcomes of CD19 CAR T in transformed indolent lymphoma compared to de novo aggressive large B-cell lymphoma. Am J Hematol. 2024;99:2178-2187.

23.

Zhang

Cai

Gao

, et al. Case report: CD19 CAR T-cell therapy following autologous stem cell transplantation: a successful treatment for R/R CD20-negative transformed follicular lymphoma with TP53 mutation. Front Immunol. 2023;14:1307242.

24.

Huang

Gong

Liu

, et al. Case report: bispecific CD20/CD30-targeted chimeric antigen receptor T-cell therapy for non-Hodgkin's lymphoma. Front Immunol. 2025;16:1567149.

25.

Spiegel

Patel

Muffly

, et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B-cell malignancies: a phase 1 trial. Nat Med. 2021;27:1419-1431.

26.

Nizamuddin

Bartlett

. Bispecific antibodies in follicular lymphoma. Haematologica. 2025;110:1472-1482.

27.

Ghione

Palomba

Patel

, et al. Comparative effectiveness of ZUMA-5 (axi-cel) vs SCHOLAR-5 external control in relapsed/refractory follicular lymphoma. Blood. 2022;140:851-860.

28.

Fukuhara

Kato

Goto

, et al. Efficacy and safety of tisagenlecleucel in adult Japanese patients with relapsed or refractory follicular lymphoma: results from the phase 2 ELARA trial. Int J Hematol. 2023;117:251-259.

29.

Britton

Mahat

Richardson

, et al. FDA approval summary: lisocabtagene maraleucel for relapsed or refractory follicular lymphoma. Clin Cancer Res. 2025;31:3830-3833.

30.

Bogucka-Fedorczuk

Wróbel

. Bispecific antibodies in the treatment of follicular lymphoma. Hematology in Clinical Practice. 2023;14:80-86.

31.

U.S. Food and Drug Administration . FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma including transformed follicular lymphoma. FDA; 2020. [Regulatory approval reference; efficacy data from SADAL trial, ref 25].

32.

Pasqualucci

Khiabanian

Fangazio

, et al. Genetics of follicular lymphoma transformation. Cell Rep. 2014;6:130-140.

33.

Kridel

Mottok

Farinha

, et al. Cell of origin of transformed follicular lymphoma. Blood. 2015;126:2118-2127.

34.

Bouska

Zhang

Gong

, et al. Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma. Leukemia. 2017;31:83-91.

35.

Schmitz

Wright

Huang

, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378:1396-1407.

36.

Chapuy

Stewart

Dunford

, et al. Molecular subtypes of diffuse large B-cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24:679-690.

37.

Lossos

Gascoyne

. Transformation of follicular lymphoma. Best Pract Res Clin Haematol. 2011;24:147-163.

38.

Dreval

Hilton

Cruz

, et al. Genetic subdivisions of follicular lymphoma defined by distinct coding and noncoding mutation patterns. Blood. 2023;142:561-573.

39.

Okosun

Wolfson

Wang

, et al. Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma. Nat Genet. 2016;48:183-188.

40.

Brodtkorb

Lingjærde

Huse

, et al. Whole-genome integrative analysis reveals expression signatures predicting transformation in follicular lymphoma. Blood. 2014;123:1051-1054.

41.

Federico

Caballero Barrigón

Marcheselli

, et al. Rituximab and the risk of transformation of follicular lymphoma: a retrospective pooled analysis. Lancet Haematol. 2018;5:e359-e367.

42.

Freeman

Kridel

Moccia

, et al. Early progression after bendamustine-rituximab is associated with high risk of transformation in advanced stage follicular lymphoma. Blood. 2019;134:761-764.

43.

Kotlov

Bagaev

Revuelta

, et al. Clinical and biological subtypes of B-cell lymphoma revealed by microenvironmental signatures. Cancer Discov. 2021;11(6):1468-1489.

44.

Sarkozy

Takata

, et al. Integrated single cell analysis reveals co-evolution of malignant B cells and tumor microenvironment in transformed follicular lymphoma. Cancer Cell. 2024;42:1003-1017.e6.

45.

Laurent

Trisal

Tesson

, et al. Follicular lymphoma comprises germinal center-like and memory-like molecular subtypes with prognostic significance. Blood. 2024;144(24):2503-2516.

46.

Radtke

Roschewski

. The follicular lymphoma tumor microenvironment at single-cell and spatial resolution. Blood. 2024;143:1069-1079.

47.

Tilly

Morschhauser

Sehn

, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386:351-363.

48.

Conconi

Ponzio

Lobetti-Bodoni

, et al. Incidence, risk factors and outcome of histological transformation in follicular lymphoma. Br J Haematol. 2012;157:188-196.

49.

Horning

Rosenberg

. The natural history of initially untreated low-grade non-Hodgkin's lymphomas. N Engl J Med. 1984;311:1471-1475.

50.

Z-H

Zhang

M-Y

Federico

, et al. Early histological transformation of follicular lymphoma to diffuse large B-cell lymphoma indicating adverse survival. Cancer. 2024;130:3321-3332.

51.

Montoto

Davies

Matthews

, et al. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol. 2007;25:2426-2433.

52.

Ghesquières

Berger

Felman

, et al. Clinicopathologic characteristics and outcome of diffuse large B-cell lymphomas presenting with an associated low-grade component at diagnosis. J Clin Oncol. 2006;24:5234-5241.

53.

Schöder

Noy

Gönen

, et al. Intensity of 18-fluorodeoxyglucose uptake in PET distinguishes between indolent and aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2005;23:4643-4651.

54.

Al-Tourah

Gill

Chhanabhai

, et al. Population-based analysis of incidence and outcome of transformed non-Hodgkin's lymphoma. J Clin Oncol. 2008;26:5165-5169.

55.

Parry

Okosun

. An updated understanding of follicular lymphoma transformation. Blood. 2025;146:1812-1823.

56.

Goyal

Magnusson

Wang

Roose

Narkhede

Seymour

. Modern, real-world patterns of care and clinical outcomes among patients with newly diagnosed diffuse large B-cell lymphoma with or without double/triple-hit status in the United States. Haematologica. 2023;108:1190-1195.

57.

NCCN Clinical Practice Guidelines in Oncology . B-cell lymphomas. Version; 2025.

58.

Madsen

Pedersen

Vase

MØ

, et al. Outcome determinants for transformed indolent lymphomas treated with or without autologous stem-cell transplantation. Ann Oncol. 2015;26:393-399.

59.

Villa

Crump

Keating

Panzarella

Feng

Kuruvilla

. Outcome of patients with transformed indolent non-Hodgkin lymphoma referred for autologous stem-cell transplantation. Ann Oncol. 2013;24:1603-1609.

60.

Ban-Hoefen

Vanderplas

Crosby-Thompson

, et al. Transformed non-Hodgkin lymphoma in the rituximab era: analysis of the NCCN outcomes database. Br J Haematol. 2013;163:487-495.

61.

Gisselbrecht

Glass

Mounier

, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28:4184-4190.

62.

Neelapu

Locke

Bartlett

, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544.

63.

Thieblemont

Phillips

Ghesquieres

, et al. Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: dose expansion in a phase I/II trial. J Clin Oncol. 2023;41:2238-2247.

64.

Noy

Schöder

Gönen

, et al. The majority of transformed lymphomas have high standardized uptake values (SUVs) on PET similar to diffuse large B-cell lymphoma (DLBCL). Ann Oncol. 2009;20:508-512.

65.

NCCN Clinical Practice Guidelines in Oncology. B-cell lymphomas. Version 2025. National Comprehensive Cancer Network.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.16 MB

0.00 MB