T-cell lymphoma following chimeric antigen receptor-T therapy: a cause for concern?

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T-cell lymphoma following chimeric antigen receptor-T therapy:
a cause for concern?

by Federico Stella, Joseph A. Fraietta, Stephen J. Schuster and Marco Ruella

Received: July 9, 2026.
Accepted: September 8, 2026.

Citation: Federico Stella, Joseph A. Fraietta, Stephen J. Schuster and Marco Ruella.
T-cell lymphoma following chimeric antigen receptor-T therapy: a cause for concern?
Haematologica. 2026 Sept 17. doi: 10.3324/haematol.2026.301592 [Epub ahead of print]

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T-cell lymphoma following chimeric antigen receptor-T therapy: a cause for concern?
Federico Stella1, 2, Joseph A. Fraietta1, 3, 4, 5, Stephen J Schuster6, 7, and Marco Ruella1,
6, 7, 8, 9*

1. Center for Cellular Immunotherapies, University of Pennsylvania, PA, USA
2. Division of Hematology and Stem Cell Transplantation, Fondazione IRCCS Istituto
Nazionale dei Tumori, Milan, Italy
3. Abramson Cancer Center, Perelman School of Medicine, University of P ennsylvania,
Philadelphia, PA
4. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA
5. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA
6. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, PA, US
7. Division of Hematology-Oncology, Hospital of the University of Pennsylvania, PA, USA
8. Cellular Therapy and Transplant Program, University of Pennsylvania, PA, USA
9. Dipartimento di Biotecnologie e Scienze della Salute, Università di Torino, Italy
*Corresponding author
Marco Ruella, MD
Address: 3400 Civic Center Blvd, PCAM 8-112, Philadelphia, PA, 19003
Office phone: +1-215-746-4880
Email: mruella@upenn.edu
Competing interests
F.S. the author declare no competing interests
J.A.F. has patents and intellectual property in T-cell-based cancer immunotherapy with
royalties; funding from Tmunity Therapeutics and Danaher Corporation; consultancy with Retro
Biosciences; and scientific advisory board membership with Cartography Bio, Shennon
Biotechnologies, CellFe Biotech, OverT Bio and Tceleron Therapeutics
S.J.S. served as a consultant to AstraZeneca, BeiGene, Celgene, Genentech, Genmab, Fate
Therapeutics, Roche, Incyte, Juno Therapeutics, Legend Biotech, Loxo Oncology, MorphoSys,
Mustang Biotech, Nordic Nanovector, Novartis and Regeneron; has received research funding
from AbbVie, Adaptive Biotechnologies, Celgene, DTRM, Genentech, Roche, Juno
Therapeutics, Merck, Novartis, Incyte, Pharmacyclics and and TG Therapeutics; has received
honoraria from Celgene and Novartis; and holds patents related to CD19 CAR T cells and
autologous costimulated T cells.
M.R. receives research funding from viTToria biotherapeutics and AbClon. M.R. is the scientific
founder of viTToria biotherapeutics.
Author contributions
F.S and M.R. conceptualized the project, interpreted and discussed the literature, and wrote the
manuscript. J.A.F and S.J.S. reviewed, provided conceptual feedback and edited the
manuscript. M.R.. supervised the project. All authors reviewed, provided critical textual additions
and approved the final manuscript.

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Abstract
Chimeric antigen receptor (CAR) T -cell therapy has revolutionized the treatment of relapsed or
refractory B-cell malignancies and multiple myeloma, with tens of thousands of patients treated
worldwide. As survival improves, long-term safety has come into focus, and rare reports of T-cell
lymphomas occurring after CAR T-cell infusion have prompted regulatory scrutiny and heightened
clinical attention.
Drawing on pivotal trials, real -world registries, meta -analyses, pharmacovigilance data, and
detailed molecular case reports, we review the incidence, biological plausibility, and clinical
relevance of lymphomas ari sing after CAR T -cell therapy. Registry data and large institutional
series consistently show that secondary T-cell malignancies are exceedingly rare, with reported
incidences of approximately 0.03 -0.3% depending on the cohort, and far less common than
therapy-related myeloid neoplasms, solid tumors, and non -melanoma skin cancers in heavily
pretreated populations. Most molecularly characterized post -CAR T -cell lymphomas lack
evidence of CAR vector -driven transformation and appear to reflect pre -existing or therapy-
selected clonal T-cell populations in the context of clonal hematopoiesis, immune dysregulation,
and, in some cases, viral reactivation. Nevertheless, rare CAR -positive cases with informative
integration-site data confirm that vector -related transformation is biologically possible, although
exceptional and probably dependent on cooperating host or clonal events.
We also discuss pathogenetic mechanisms, diagnostic pitfalls, and practical recommendations
for surveillance and patient counseling.
In co nclusion, secondary T -cell lymphomas represent a concerning but extremely uncommon
complication of CAR T -cell therapy. Vigilance through standardized long -term follow -up and
rigorous molecular investigation of suspected cases is warranted, but current evidence does not
undermine the overwhelmingly favorable benefit-risk profile of CAR T-cell therapy.

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Main text
1) Introduction
Chimeric antigen receptor (CAR) T-cell therapy has transformed the management of relapsed or
refractory B-cell lymphoma, acute lymphoblastic leukemia, and multiple myeloma. With multiple
commercially approved products and tens of thousands of patients treated worldwide, CAR T
cells are now firmly established as a standard of care for diseases that historically carried dismal
prognoses1–9. As durable remissions and long-term survival have become increasingly common
in a subset of CAR T -treated patients, attention has progressively shifted from early toxicities,
such as cytokine release syndrome and immune effector cell -associated neurotoxicity, to long-
term safety. Beginning in late 2023 10 and continuing through 2024 11 the US Food and Drug
Administration (FDA) and the European Medicines Agency (EMA) Pharmacovigilance Risk
Assessment Committee (PRAC)12 highlighted rare reports of T-cell malignancies occurring after
CAR T -cell therapy, prompting class -wide label updates and recommendations for lifelong
surveillance13. These communications were appropriately triggered by post marketing reports,
emerging case reports, and pharmacovigilanc e signals that raised the possibility of CAR -
associated T-cell lymphomagenesis. Given the well-established historical precedent of insertional
mutagenesis in early gene therapy trials 14, such reports understandably generated concern
among clinicians, regul ators, and patients. However, interpreting these events requires careful
contextualization.
CAR T-cell recipients represent a uniquely vulnerable population, typically exposed to multiple
lines of cytotoxic and immunosuppressive therapies, frequently har boring clonal hematopoiesis,
and experiencing profound immune perturbation 15–19. Disentangling events causally attributable
to CAR T -cell products from those reflecting background or therapy -related risk, therefore,
remains challenging. This review aims to critically examine the current evidence on lymphomas
arising after CAR T-cell therapy, with a specific focus on T -cell malignancies. We integrate data
from national and international registries, pivotal and large clinical trials, real -world cohorts, and
molecularly characterized case reports to define the best available incidence, explore
pathogenetic mechanisms, and outline clinical and regulatory implications of post -CAR T -cell
lymphoid malignancies. Our goal is to provide a balanced perspective grounded in denominators
rather than anecdotes, emphasizing vigilance without alarm in the interpretation of these rare
events.
2) Global exposure to CAR T -cell therapy and secondary malignancies: defining the
denominator and contextualizing T-cell lymphomas
Any assessment of late safety signals following CAR T -cell therapy critically depends on an
accurate definition of the population at risk. While exact denominators vary according to region
and reporting system, available estimates indicate that more than 40,000 patients worldwide have
been treated with autologous CAR T-cell products across hematologic indications, including large
B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, acute lymphoblastic leukemia,
chronic lymphocytic leukemia, and multiple myeloma20–23. As CAR T -cell therapy moves into
earlier treatment lines and additional diseases, the rapidly growing use of this therapy makes
reliable denominators essential for interpreting rare adverse events.

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The first signal assessments relied heavily on spontaneous reporting systems, most notably the
US FDA Adverse Event Reporting System (FAERS) 24. While indispensable for signal detection,
such systems are inherently limited by underreporting, reporting bias, lack of standardized
adjudication, and, mo st importantly, the absence of a true denominator. Consequently,
pharmacovigilance databases cannot provide population -based incidence estimates and may
either inflate perceived causality or miss unreported events. Registry -based data offer a more
robust framework for contextualizing late events. National and multicenter registries are better
positioned to capture consecutive patients, apply standardized definitions, and enable longitudinal
follow-up (Table 1).

At an international level, the Center for In ternational Blood and Marrow Transplant Research
(CIBMTR) captured 11,345 recipients of commercial CAR T -cell therapies through December
2023, including 8,060 patients enrolled in formal post-authorization safety studies with a median
follow-up of 13 months25. Within this cohort, 565 secondary or subsequent malignant neoplasms
were reported, predominantly non -melanoma skin cancers and therapy -related myeloid
neoplasms, whereas three T -cell malignancies were identified, none showing aberrant CAR
expression b y routine clinical immunophenotyping, although this is not equivalent to vector -
specific molecular exclusion 25. The French DESCAR -T registry reported a single T -cell
malignancy among 3,066 patients treated with commercial CAR T -cell products since 2018,
corresponding to an incidence of approximately 0.03% 26. Prospective real -world data further
support this interpretation. In the Italian CART-SIE database, secondary primary malignancies
(SPM) were observed in 4% of 651 CAR T -cell-treated patients, a frequen cy consistent with
expectations for heavily pretreated lymphoma populations 27. As in other studies, the burden of
secondary malignancies was driven largely by myeloid neoplasms and solid tumors, while T-cell
malignancies represented an exceptionally rare s ubset, accounting for only 2 of 651 patients
(0.3%)27. Large registry studies and meta -analyses provide the necessary denominators to
contextualize the risk of secondary primary malignancies after CAR T-cell therapy. A systematic
review and meta-analysis including more than 5,500 patients treated with approved CD19 - and
BCMA-directed CAR T cells reported an overall SPM incidence of approximately 6%, with
hematologic malignancies representing the most frequent category and T -cell malignancies
accounting for 1.5% of all SPM events 28. Importantly, randomized trials comparing CAR T -cell
therapy with standard-of-care strategies have not demonstrated an excess risk of SPMs in the
CAR T-cell arms within currently available follow-up29–33; however, trial follow-up remains too short
to exclude very late or very rare events. Similar conclusions emerged from large single-institution
and national registry experiences, in which the cumulative incidence of second malignancies was
driven predominantly by myelodysplastic sy ndromes, acute myeloid leukemia, and solid
tumors34,35.

Taken together, these data indicate that SPMs following CAR T -cell therapy are more readily
explained by background risk and cumulative treatment exposure than by a broad CAR -specific
oncogenic effect. Within this broader landscape, T-cell lymphomas occupy a numerically marginal
but biologically distinctive position. Their rarity contrasts with the attention they have received,
driven by the theoretical concern that genetically modified T cells might undergo malignant
transformation. This biological specificity, rather than numerical impact, provides the rationale for

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examining T -cell lymphomas separately from the more common and better -characterized
spectrum of secondary malignancies.

3) T-cell lymphomas after CAR T-cell therapy: case-based evidence
Reports of T -cell lymphomas arising after CAR T -cell therapy encompass a biologically
heterogeneous group of entities that can be broadly categorized into three non-mutually exclusive
scenarios (Figure 1): 1) CAR-negative T-cell lymphomas arising in the post -CAR T-cell setting
(Table 2 ) 2) CAR -positive T -cell malignancies with demonstrable involvement of the CAR
transgene ( Table 3 ), and 3) clonal T -cell proliferations or “mimickers” that may simulate
lymphoma but follow a benign or self -limited course ( Table 2 ). This classification requires
molecular caution: detection of low-level CAR sequences in a biopsy may reflect admixed CAR T
cells rather than a malignant CAR-transduced clone.

3.1) CAR-negative T-cell lymphomas after CAR T-cell therapy. Most molecularly adjudicated
T-cell lymphomas reported after CAR T -cell therapy do not show evidence of CAR transgene
expression or integration. In the wake of the FDA safety communication, Ghilardi et al. provided
one of the first detailed biological analyses of this concern, reporting a peripheral T-cell lymphoma
that developed three months after commercial axi-cel CD19 CAR T-cell therapy. In this case, low
CAR transgene levels were attributable to infiltrating CAR T cells rather than malignant
transformation. Deep clonotypic and genomic analyses demonstrated that the neoplastic T -cell
clone was already detectable at very low frequency before CAR T-cell infusion, supporting a pre-
existing clonal origin rather than CA R-driven oncogenesis 36. Hamilton et al. later described a
lethal Epstein -Barr virus (EBV) -positive T -cell lymphoma arising after axicabtagene ciloleucel
infusion, in which extensive molecular profiling excluded oncogenic vector integration and instead
revealed shared DNMT3A and TET2 mutations consistent with clonal hematopoiesis34. Additional
CAR-negative events have been reported beyond single -case mechanistic studies, including a
PTCL-NOS after liso-cel with no detectable CAR transgene37.

These observati ons are most consistent with indirect pathogenetic mechanisms, whereby
profound immune perturbation following lymphodepletion and CAR T -cell expansion associated
with an inflammatory milieu may permit the outgrowth of pre -existing malignant or premalignant
T-cell clones. In this scenario, CAR T-cell therapy might function as a permissive or accelerating
factor rather than a direct oncogenic driver38.

3.2) CAR-positive T-cell malignancies – Molecularly definitive evidence that CAR -modified T
cells can becom e a malignant clone has been provided by a small number of molecularly
characterized cases. Ozdemirli et al. reported an indolent CD4 ⁺ cytotoxic T -cell lymphoma
involving the gastrointestinal tract in a patient treated with ciltacabtagene autoleucel for mu ltiple
myeloma, in which CAR gene expression was detected in tumor cells and whole -genome
sequencing identified a single lentiviral integration site within the SSU72 gene 39. Although the
clinical course was relatively indolent, this case established biological plausibility without proving
that integration alone was sufficient for transformation. More aggressive phenotypes have also
been described. Kobbe et al. reported a rapidly progressive peripheral T-cell lymphoma occurring
approximately one month after tisagenlecleucel infusion, in which the malignant clone expressed

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the CAR transgene and harbored multiple lentiviral integration sites 40. Notably, the same T -cell
clone was retrospectively detectable at low frequency prior to CAR T -cell manufacturing,
suggesting expansion of a pre-existing population rather than de novo transformation.
Perica et al. later reported an indolent CD4⁺ T-cell lymphoma of the gastrointestinal tract arising
after BCMA -directed CAR T -cell therapy, in which high -resolution integrati on site analysis
demonstrated lentiviral CAR insertion within the TP53 tumor suppressor gene, providing one of
the clearest examples in which insertional mutagenesis may have contributed to malignant
transformation41. Finally, Braun et al . described a leuk emic peripheral T -cell lymphoma
developing after sequential exposure to BCMA -directed CAR T cells and a GPRC5D -directed
bispecific antibody, in which longitudinal single-cell multiomic profiling revealed clonal expansion
of CAR-expressing T cells originating from a TET2-mutated precursor, highlighting the role of pre-
existing clonal vulnerability combined with chronic antigenic stimulation42.

At the population level, CAR-positive T-cell malignancies remain exceptional. Collectively, these
observations indicate that insertional mutagenesis or CAR -driven transformation is possible but
occurs in an exceedingly small minority of patients. Notably, the level of mechanistic resolution
varies substantially across reports; the most informative cases combine sensitive CAR detection
with integration -site mapping and longitudinal clonotypic analyses, thereby allowing a clearer
distinction between CAR-derived transformation and the expansion of pre-existing clones.

3.3) Mimickers and diagnostic pitfalls . Adding fur ther complexity, not all clonal T -cell
proliferations observed after CAR T -cell therapy represent autonomous malignant lymphomas.
For example, Maurer et al. reported a clonally expanded nodal T -cell population with histologic
features suggestive of T -cell lymphoma that arose during acute infection and subsequently
regressed spontaneously, with no detectable CAR transgene by whole -genome sequencing 43.
Along the same spectrum of diagnostic mimickers, Capes et al. described severe post-CAR T-
cell cytopenias driven by an oligoclonal expansion of large granular lymphocyte–like CD8⁺ T cells
in the bone marrow, lacking CAR expression and responsive to immunosuppressive therapy,
underscoring how reactive clonal T -cell proliferations may masquerade as malignant proce sses
in the post-CAR T-cell setting44.
Further supporting this diagnostic caution, Ho et al. recently described a case of massive CD4 -
skewed cilta-cel expansion associated with immune -related adverse events, in which extensive
TCR repertoire and vector integration analyses showed polyclonal CAR T-cell expansion without
evidence of clonal dominance or malignant transformation45.

Such cases highlight the risk of overdiagnosis and overtreatment if clinical, pathological, and
molecular data are not integrated longitudinally and reconciled with the clinical tempo38. Together,
case-based evidence underscores that T -cell lymphomas after CAR T -cell therapy represent a
spectrum of entities with distinct biological underpinnings, ranging from rare CAR -derived
malignancies to indirect, therapy-associated lymphomas and benign mimickers.

4) Pathogenetic mechanisms: disentangling causality
Understanding the biological basis of T-cell lymphomas arising after CAR T-cell therapy requires
disentangling causality from coinci dence in a profoundly perturbed immunologic landscape.

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Available evidence supports a multifactorial model in which direct CAR -related mechanisms
appear to account for only a minority of cases, while indirect processes predominate.

4.1) Expansion of pre-existing clonal T-cell populations. A recurring theme across molecularly
characterized cases is the presence of pre -existing clonal T -cell or hematopoietic populations
detectable before infusion or in the manufactured product. Retrospective analyses have
demonstrated that the malignant clone was present at low frequency in the apheresis product or
even months to years earlier, prior to CAR T -cell manufacturing 40. In such cases, CAR
transduction, manufacturing, and subsequent in vivo expansion may select for o r amplify an
already abnormal clone rather than initiate transformation de novo. This concept is further
supported by reports of oligoclonal or monoclonal T-cell expansions following CAR T-cell therapy
that do not invariably progress to overt lymphoma 43. T hese expansions highlight the potent
selective pressures imposed by lymphodepleting chemotherapy, homeostatic cytokine signaling,
and antigen-driven proliferation in the post-infusion period.

4.2) Clonal hematopoiesis and shared mutational landscapes – Clonal hematopoiesis of
indeterminate potential (CHIP), particularly involving epigenetic regulators such as DNMT3A and
TET2, has emerged as a key predisposing factor. Recent studies have shown that CHIP is
detectable in approximately 25% to 50% of patients undergoing CAR T-cell therapy15–19, reflecting
the heavy pretreatment and advanced age typical of this population. Several post -CAR T-cell T-
cell lymphomas share CHIP-associated mutations between malignant T cells and non-malignant
hematopoietic compartmen ts, indicating a common ancestral clone 34,42. Beyond its role as a
reservoir of premalignant clones, CHIP is increasingly recognized as a pro -inflammatory state.
Loss-of-function alterations in TET2 and DNMT3A can enhance myeloid-cell inflammatory output,
including activation of inflammasome-related pathways and increased production of IL -1β, IL-6,
and other inflammatory mediators. Mechanistically, TET2 -deficient macrophages have been
shown to up -regulate IL -1β through both transcriptional derepression and enhanced NLRP3
inflammasome-dependent processing, whereas DNMT3A or TET2 loss can also trigger
mitochondrial DNA release, cGAS activation, and type I interferon signaling in human
macrophages. These observations provide a biological basis for linking CHIP -associated
epigenetic lesions to exaggerated innate immune activation rather than viewing CHIP solely as a
passive marker of prior therapy or aging46–48. This is particularly relevant in the CAR T-cell setting,
where lymphodepletion, immune reconstitution, CAR T -cell expansion, CRS, infections, and
prolonged cytopenias generate a highly inflammatory post -treatment milieu. Such inflammation
may provide both a proliferative advantage and a selective pressure for pre-existing CHIP-derived
hematopoietic clones, including rare clones with lymphoid or multilineage potential, although this
remains incompletely proven in individual cases. These mutations may therefore confer increased
fitness, genomic instability, or altered differentiation potential, lowering the threshold for malignant
progression under immune stress. In this framework, CAR T -cell therapy acts as a biological
stress test that unmasks latent clonal vulnerabilities rather than serving as the primary oncogenic
insult.

4.3) Immune dysregulation and viral reactivation. Profound immune perturbation is a defining
feature of CAR T -cell therapy. Lymphodepleting chemotherapy, followed by rapid immune

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reconstitution that can be shaped by CAR -modified cells creates a permissive environment for
dysregulated imm une responses. B -cell aplasia, hypogammaglobulinemia, and prolonged
cytopenias further impair immune surveillance. This spectrum of hematologic toxicity is now
recognized as immune effector cell -associated hematotoxicity (ICAHT), a distinct and frequent
complication of CAR T -cell therapy that differs qualitatively from conventional chemotherapy -
induced myelosuppression. ICAHT may occur early or late after infusion and reflects the
combined effects of lymphodepletion, baseline hematopoietic reserve, systemic inflammation,
bone marrow microenvironment injury, and CAR T -cell-driven immune activation. Severe or
prolonged ICAHT is clinically relevant because it predisposes patients to bacterial, fungal, and
viral infections, contributes to non-relapse mortality, and may mark a sustained state of impaired
immune surveillance rather than a transient cytopenic phase. Rejeski et al. specifically emphasize
that hematologic toxicity after CAR T-cell therapy is common, can predispose to clinically relevant
infections, and has now been formalized through EHA/EBMT grading into early and late ICAHT18.
Emerging data also suggest that delayed immune reconstitution may have consequences beyond
infection. Exploratory abstract -level data from a single -center retrospective analysi s at the
University of Pennsylvania further support a possible link between prolonged immune dysfunction
and secondary malignancy risk after CAR T-cell therapy. In this cohort of 284 patients with B-cell
lymphoma, Chong and colleagues reported non-melanoma skin cancers in 21 patients (7%) after
CAR T-cell therapy. Failure to recover an absolute lymphocyte count ≥1 × 10³ cells/µL, as well as
longer time to lymphocyte recovery, was associated with a higher risk of non -melanoma skin
cancer. Although these findings remain preliminary and require confirmation in full peer-reviewed
datasets, they suggest that delayed lymphocyte recovery may represent a clinically informative
marker of persistent immune dysfunction after CAR T-cell therapy49.
Several reported T -cell lymphomas after CAR T -cell therapy have also been associated with
Epstein–Barr virus positivity, supporting a role for viral reactivation in lymphomagenesis under
conditions of immune suppression 34. In such cases, the temporal association with CAR T -cell
infusion likely reflects a broader state of post-treatment immune dysregulation rather than a direct
vector-mediated effect.

4.4) Insertional mutagenesis: rare but biologically plausible . Genetic modification of T cells
using integrating vectors inhere ntly carries a theoretical risk of insertional mutagenesis. This
concern is grounded in historical experience from early gene therapy trials, in which retroviral
integration near proto -oncogenes led to malignant transformation 14. In the CAR T -cell setting,
however, extensive clinical experience with lentiviral and gammaretroviral vectors has
demonstrated a reassuring long-term safety profile in large clinical cohorts, although the available
data do not eliminate rare, patient -specific events38,50. This conclusion is further supported by a
large long -term follow -up study of 783 patients treated across 38 trials with lentiviral or
gammaretroviral gene-modified T-cell therapies, encompassing more than 2,200 patient-years of
observation. In that analysis, 18 pat ients developed secondary malignancies, but tumor vector -
copy-number testing and integration -site analyses did not support vector -mediated insertional
mutagenesis; one T-cell lymphoma was observed, but the malignant T cells were not marked by

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vector integr ation51. Nevertheless, rare cases provide proof of principle. CAR -positive T -cell
malignancies with demonstrable vector integration into host genomic loci have been reported,
including insertion within genes implicated in transcriptional regulation or cell-cycle control21,34–36.
Importantly, several reported cases of CAR-associated T-cell malignancies show multiple vector
integration sites without clear enrichment near canonical oncogenes, suggesting that vector
insertion alone is unlikely to be sufficient to drive malignant transformation38. This observation is
consistent with the integration profile of modern self -inactivating lentiviral vectors and
contemporary gamma-retroviral systems, which generally have lower enhancer-promoter activity
than early gene-therapy vectors.
Non-viral systems illustrate a related but distinct risk. Transformation events have also been
reported with piggyBac transposon -engineered CAR T cells, in which CAR -expressing T -cell
lymphomas showed high transgene copy numbers and com plex genomic alterations 52,
highlighting that transgene copy number, genomic instability, and clonal selection may matter at
least as much as the identity of the integration platform. These include the two product -derived
CAR T -cell lymphomas reported in t he Australian CARTELL trial of donor -derived piggyBac-
modified CD19 CAR T cells, one presenting as a retroperitoneal CD4 -positive CAR T -cell
lymphoma and the second detected as an asymptomatic thoracic para-aortic/mediastinal CAR T-
cell tumor during post-trial screening53.

Taken together, these observations argue against a simple linear model of CAR -driven
oncogenesis and instead support a multistep process requiring cooperating events, including pre-
existing clonal hematopoiesis, oncogenic mutations, pos sible chronic antigenic stimulation, and
selective pressures imposed during CAR T-cell manufacturing and in vivo expansion.

4.5) An integrated multistep model. Taken together, available data support a multistep model
in which T-cell lymphomas after CAR T-cell therapy arise from the convergence of predisposing
host factors and therapy -induced selective pressures ( Figure 1 ). Pre -existing clonal
abnormalities, clonal hematopoiesis, or latent viral infection provide the substrate, while
lymphodepletion, inflam matory cytokine milieus, and CAR -driven expansion may act as
accelerants. Rarely, CAR vector integration may contribute as an additional cooperating event,
rather than as a sole driver. This integrated model reconciles the biological plausibility of CAR -
related oncogenesis with the exceptionally low incidence observed in large registries and provides
a rational framework for diagnostic evaluation, risk communication, and surveillance.

5) Clinical implications: diagnosis, monitoring, and patient counseling
Although T-cell lymphomas reported after CAR T-cell therapy are extremely rare and biologically
heterogeneous, they have important practical implications for clinical management. The principal
challenge is to ensure timely recognition of true malignant eve nts while avoiding overdiagnosis
and overtreatment of transient or reactive T-cell proliferations.

5.1) Diagnostic approach. Any new or progressive lymphadenopathy, extranodal lesion, or
unexplained systemic symptoms arising after CAR T-cell therapy should prompt tissue diagnosis
whenever feasible. Excisional biopsy or multiple core biopsies are preferred over fine -needle
aspiration to enable comprehensive histologic, immunophenotypic, and molecular assessment.

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A minimal diagnostic work -up should include: (i) full histopathologic evaluation with extended
immunohistochemistry, (ii) assessment of T -cell receptor clonality, and (iii) Epstein –Barr virus
testing. Given the central question of causality, evaluation for CAR transgene presence should
be pursued in suspected cases, and whenever feasible the original product lot, vector map,
apheresis/manufacturing material, and pre -infusion samples should be retrieved, ideally using
sensitive molecular approaches rather than immunophenotyping alone, which may lack sensitivity
or fail to detect truncated or transcriptionally silent constructs54.
Recommended methods include quantitative PCR (qPCR) or digital droplet PCR (ddPCR)
targeting vector-specific sequences (such as the CAR transgene, WPRE element, or lentiviral
LTR), next -generation sequencing -based assays for vector detection, and RNA -based
approaches to identify CAR transcripts when transcriptionally active constructs are present. In
addition, flow cytometry using anti -idiotype antibodies or CAR -specific detection reagents may
provide supportive evidence but should not be considered definitive in isolation. A major practical
limitation is the lack of standardized reagents, assay platforms, and reporting thresholds for CAR
detection across centers. This is particularly relevant because sensitivity and specificity may vary
substantially depending on the target sequence, primer/probe design, antibody reagent, and the
availability of product -specific reference material. When CAR positivity is detected or strongly
suspected, further molecular characterization, including vector copy number quantification and
integration site analysis using techniques such as linear amplification –mediated PCR (LAM -
PCR)55, ligation -mediated PCR, or targeted next -generation sequencing, may provide critical
mechanistic insight by determining whether the malignant clone derives from CAR -modified T
cells and by identifying potential integration events near cancer -related genes. However, these
analyses currently remain restricted to specialized research or reference laboratories, and results
should be interpreted with hematopathology, treating-center, manufacturer, and regulatory input.
Importantly, detection of T-cell clonality alone should not be equated with malignancy. Clonal T -
cell expansion s may occur in reactive or inflammatory settings, particularly in the context of
immune reconstitution, infection, or cytokine-driven proliferation following CAR T-cell therapy.

5.2) Diagnostic pitfalls and dynamic assessment. Several reported cases highlight that clonal
T-cell proliferations after CAR T -cell therapy may follow a self -limited course, including
spontaneous regression without lymphoma -directed treatment. In clinically stable patients with
atypical or borderline findings, short-interval reassessment with repeat imaging or biopsy may be
appropriate before initiating aggressive therapy. This dynamic approach is particularly relevant
when clinical presentation coincides with intercurrent infection or inflammatory triggers.
Conversely, rapidly progressive disease, organ compromise, or unequivocal histologic features
of aggressive T-cell lymphoma warrant prompt treatment according to standard T-cell lymphoma
guidelines, independent of CAR transgene status.

5.3) Monitoring and follow -up. Given the absence of a validated screening strategy and the
exceedingly low incidence of T-cell malignancies, routine surveillance specifically targeting these
events is not justified beyond product-label and guideline-recommended long-term follow-up after
CAR T -cell therapy. Lifelong clinical monitoring should focus on new symptoms, unexplained
cytopenias, and persistent lymphadenopathy, integrated within existing survivorship programs. At
present, there is insufficient evidence to support systematic pre -infusion screening for clonal T -

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cell populations or clonal hematopoiesis solely to mitigate this rare risk of post -CAR T -cell
lymphomas. This does not exclude a potential role for CHIP assessment in other contexts,
including risk stratification for therapy -related myeloid neoplasms, prolonged cytopenias,
inflammatory toxicity, or other CAR T -cell outcomes; however, its use specifically to prevent or
predict post-CAR T-cell lymphomas remains unsupported by current evidence. Such approaches
remain investigational.

5.4) Patient counseling – Patient communication should emphasize that T-cell lymphomas after
CAR T-cell therapy are exceptionally rare and that the overall benefit -risk profile of CAR T -cell
therapy remains overwhelmingly favorable for approved indi cations. Transparent discussion of
long-term follow-up requirements and prompt reporting of new symptoms should be encouraged,
while avoiding alarmist framing that could undermine confidence in a highly effective therapy.

6) Conclusions
Research in the field of chimeric antigen receptor (CAR) T-cell therapy is currently evolving along
two complementary directions. On one hand, substantial efforts aim to improve efficacy and
expand clinical indications, including the exploration of novel target antigens 56,57, optimization of
CAR design 58, and advances in cell manufacturing strategies 59. On the other hand, increasing
attention is being devoted to improving safety 60, both by mitigating acute toxicities and by
understanding and preventing potential long -term co mplications. Within this broader context,
lymphomas arising after CAR T -cell therapy represent a rare but biologically informative
phenomenon that has prompted substantial clinical and scientific attention, despite their very low
observed incidence. When evaluated against robust denominators from national and international
registries, T -cell malignancies following CAR T -cell therapy occur at an exceedingly low
frequency, well below 1% in available registry datasets, with important caveats related to follow-
up duration, product mix, and ascertainment in heavily pretreated oncohematologic populations61.

Accumulating molecular evidence indicates that most reported cases are not primarily driven by
CAR vector integration. Instead, they reflect the convergence of pre-existing clonal vulnerabilities,
clonal hematopoiesis, viral reactivation, and profound immune perturbation in heavily pretreated
patients. Rare CAR-positive T-cell malignancies with demonstrable transgene integration confirm
biological plausibility but appear to require additional cooperating events and remain exceptional.
From a clinical perspective, these observations underscore the importance of careful diagnostic
evaluation rather than routine surveillance for an exceedingly rare complication. I ntegration of
histopathology, molecular clonality, viral studies, and sensitive assays for CAR detection is
essential to distinguish true malignant transformation from reactive or self -limited T -cell
proliferations. Avoiding overtreatment of benign mimickers is as critical as recognizing aggressive
disease when it occurs. Regulatory and pharmacovigilance efforts have appropriately
emphasized systematic reporting and long-term follow-up, enabling continued refinement of risk
estimates without restricting access to highly effective therapies. Importantly, the available body
of evidence does not support a reassessment of the overall benefit–risk balance of CAR T -cell
therapy, which remains overwhelmingly favorable.

12

In conclusion, T -cell lymphomas following CAR T-cell therapy should prompt vigilance,
standardized investigation, transparent reporting, and continued data collection, but not alarm. As
CAR T -cell therapy expands to earlier lines of treatment and new indications, ongoing
collaborative surveillance will further clarify rare late effects while preserving the transformative
impact of this therapeutic modality.

13

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20
Tables
Table 1. T-cell malignancies reported after CAR T-cell: Registry-based denominators and
incidence estimates.
Study Patients CAR T-cell
product(s)
Follow-up Secondary
malignancies
T-cell
malignancies
CAR
integration
DESCAR-T Registry,
France
(Dulery et al., Nat Med 2025)
3,066
Commercial
anti-CD19 &
anti-BCMA
Median
12.7–17.7
months
- 1 case
(0.03%)
Yes
Integration
in PLAAT4
CIBMTR
(Levine et al, Nat Med 2024) 11,345 Commercial 13 months 565 SPM
(4.9%)
3 cases
(0.03%) No
CART-SIE Database,
Italy
(Barone et al., BJH 2024)
651 Commercial
anti-CD19 12.2 months 28 SPMs
(4.3%)
2 cases
(0.3%) No

21
Table 2. CAR-negative T-cell lymphomas and mimickers.
Reference Product Time Key biology Interpretation
Ghilardi et al., Nat Med
2024 axi-cel ~3 months
Dominant TCR
clone detectable
pre-infusion
Pre-existing clonal TCL
unmasked post-CAR T; not
CAR-driven
Hamilton et al., NEJM
2024 axi-cel 54 days
EBV+,
DNMT3A/TET2
CHIP
Indirect mechanism
Tatetsu et al., IJH 2025 liso-cel 8 months PTCL-NOS, CAR
not detected Therapy-associated TCL
Maurer et al., Nat
Commun 2025 axi-cel During infection
Clonal TFH-like
expansion,
regression
Diagnostic mimicker
Capes et al., BJH 2025 axi-cel
Variable (post-
infusion
cytopenia
phase)
Oligoclonal CD8+
LGL–like marrow T-
cell expansion;
CAR-negative;
immune-mediated
cytopenias;
response to
immunosuppression
Reactive LGL-like clonal
expansion; diagnostic
mimicker, not lymphoma
Ho et al., Nat Med 2026 cilta-cel
Day 13 peak
expansion;
CirAEs from day
31 onward
Extreme CD4-
skewed CAR T-cell
hyperexpansion;
diverse TCR Vβ
repertoire; no clonal
dominance by
vector integration
analysis; IL-15–
CCL5–CCR5 axis
implicated
Polyclonal, non-malignant
CAR T-cell hyperexpansion
causing immune-related
toxicity; diagnostic mimicker,
not lymphoma

22
Table 3. Case report CAR-positive T-cell malignancies.
Reference Indication/
Product
Time to
onset
Histology
phenotype
Molecular
findings
Interpretation
Ozdemirli et al., NEJM 2024 MM / cilta-cel ~4–8
months
Indolent CD4+
cytotoxic GI TCL
CAR+, insertion
in SSU72
CAR-derived lymphoma;
integration not
necessarily sole driver
Kobbe et al., NEJM 2024 LBCL / tisa-
cel
~1
month Aggressive PTCL CAR+, multiple
integration sites
Expansion of pre-
existing clone
Perica et al., NEJM 2025 MM / cilta-cel ~2
months
Indolent CD4+ GI
T-cell lymphoma /
LPD
Lentiviral
integration in
TP53 and
TANGO2.
Strong insertional
mutagenesis signal
involving TP53 with
cooperating events
Braun et al., Nat Med 2025
MM / cilta-
cel; then
talquetamab
9
months
Leukemic PTCL
with cutaneous
and intestinal
involvement; T-
LGLL-like
features
Two CAR+
clones; multiple
integration sites;
clonal evolution
from TET2-
mutated
precursor
Multistep model: pre-
existing clonal
vulnerability plus
therapy-driven selection
Dulery et al., Nat Med 2025 DLBCL / tisa-
cel 3 years
Primary
cutaneous
CD30+ TCL
Integration in
PLAAT4
Exceptional CAR-
positive event; causality
plausible

23

Figure 1 – Proposed pathogenetic model of T -cell lymphomagenesis after CAR T -cell
therapy

Host predisposition, including clonal hematopoiesis, pre -existing T-cell clones, and latent viral
infection, may interact with CAR T-cell manufacturing, lymphodepletion, cytokine-driven immune
activation, and therapy -induced selective pressures. These events may lead to reactive/self -
limited T-cell expansions, secondary CAR-negative T-cell lymphomas, or, rarely, CAR-positive T-
cell malignancies driven by vector integration.