Secondary T-cell Lymphoma Following CAR T-cell Therapy: Incidence and Potential Causes

Secondary malignancies, including T-cell lymphomas, have emerged as a significant concern following chimeric antigen receptor (CAR) T-cell therapy. While CAR T-cell therapy has demonstrated remarkable success in treating hematologic malignancies, concerns have arisen regarding its potential to induce secondary malignancies, particularly T-cell lymphomas. This article aims to provide an in-depth exploration of secondary T-cell lymphomas following CAR T-cell therapy, with a focus on incidence rates and potential underlying causes.

Incidence Rates of Secondary T-cell Lymphomas

The incidence of secondary T-cell lymphomas following CAR T-cell therapy remains a subject of research. Several case reports and retrospective studies have shed light on this rare but clinically significant phenomenon. A retrospective analysis of patients treated with CD19-targeted CAR T-cell therapy reported secondary T-cell lymphomas in approximately 1-2% of cases.¹ Furthermore, studies focusing on other CAR-T cell types, such as ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), have reported instances of secondary T-cell lymphomas, albeit at varying frequencies.²

Potential Causes of Secondary T-cell Lymphomas

The etiology of secondary T-cell lymphomas following CAR T-cell therapy remains complex and not fully elucidated. Several hypotheses have been proposed to explain the potential mechanisms underlying the development of these secondary malignancies:

Genetic alterations. CAR T-cell therapy may induce genetic alterations in T cells, leading to their malignant transformation.³
Immunosuppression. CAR T-cell therapy can induce profound immunosuppression, compromising the immune system's ability to surveil and eliminate nascent malignant cells, thereby creating a permissive environment for the development and progression of secondary T-cell lymphomas.⁴
Viral integration. The use of viral vectors in CAR T-cell transduction carries the risk of random genomic integration, which may disrupt tumor suppressor genes or activate oncogenes, predisposing to T-cell lymphomas.⁵
Inflammatory responses. The intense inflammatory responses elicited by CAR T-cell therapy may contribute to tissue damage and chronic inflammation, both of which have been implicated in carcinogenesis.⁶

Conclusion

Secondary T-cell lymphomas following CAR T-cell therapy represent a rare but clinically significant complication. Ongoing surveillance and research are essential to better understand the underlying mechanisms and risk factors associated with these secondary malignancies. Clinicians should remain vigilant in monitoring patients following CAR T-cell therapy for signs of secondary malignancies, and future studies should focus on optimizing CAR-T cell design and minimizing potential risks to ensure the long-term safety and efficacy of this transformative therapy.

References

Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. doi:10.1056/NEJMoa1709866
Anderson LD. Idecabtagene vicleucel (ide-cel) CAR T-cell therapy for relapsed and refractory multiple myeloma. Future Oncol. 2022;18(3):277-289.
Eyquem J, Mansilla-Soto, J, Giavridis T, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113-117.

Teachey DT, Lacey SF, Shaw PA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6(6):664-679.
Wang X, Rivière I. Genetic engineering and manufacturing of hematopoietic stem cells. Mol Ther Methods Clin Dev. 2017;5:96-105.
Bonifant CL, Jackson HL, Brentjens RJ, et al. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics. 2016;3:16011.
Munshi NC, Anderson LD, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-716.

Dr. Ombada indicated no relevant conflicts of interest.

Acknowledgment: This article was edited by Drs. Miriam Osei and Julian Sprague. Faculty review was performed by Drs. Teresa Gentile and Adam Binder.

A 26-year-old man was initially diagnosed with stage IVa diffuse large B-cell lymphoma (DLBCL) in 2009, when he presented with persistent symptoms of redness, itching, and double vision in the left eye. Paranasal computed tomography (CT) revealed a mass in the left frontal and ethmoid sinuses. Endoscopic biopsy and bone marrow (BM) biopsy confirmed DLBCL with BM involvement. He was treated with four cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), resulting in a complete remission. In 2017, the patient experienced difficulty swallowing, with a positron emission tomography (PET)-CT scan revealing a hypermetabolic mass in the right tonsil. Biopsy confirmed relapsed DLBCL, and the patient underwent four cycles of R-CHOP and two cycles of R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone), achieving a complete remission again. The patient did not routinely attend follow-up appointments.

In 2022, the patient was hospitalized with a femur fracture, which led to the detection of disease relapse upon biopsy. PET-CT showed widespread lymphoma involvement. He was treated with one cycle of R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). The patient declined to proceed with further chemotherapy and autologous hematopoietic cell transplantation (HCT) at that time. In 2023, the patient presented to the hospital with altered mental status characterized by nonsensical speech and was subsequently diagnosed with central nervous system (CNS) relapse of his DLBCL. A ventriculoperitoneal shunt was placed to manage increased intracranial pressure, with high-dose methotrexate administered for secondary CNS lymphoma. Following four cycles of high-dose MATRix (methotrexate, cytarabine, thiotepa, and rituximab), the patient underwent autologous HCT with CBV (cyclophosphamide, carmustine, and etoposide) conditioning in November 2023. Following successful engraftment, the patient was discharged from the BM transplant unit without any complications.

Seven months post-transplant, the patient developed severe anemia with reticulocytopenia (hemoglobin: 5.8 g/dL; hematocrit: 16.1%; mean corpuscular volume: 95.4 fL; mean corpuscular hemoglobin: 30.4 pg; reticulocyte count: 0.2%). Blood smear confirmed normochromic-normocytic anemia without additional abnormalities, prompting further investigation.

Table. Differential diagnosis of anemia in hematopoietic cell transplant recipients

Etiology	Evaluation
Reticulocytopenia
Nutritional deficiency	Iron, B12, folate measurement
Pure red cell aplasia	Parvovirus B19 DNA PCR, isohemaglutinin titer (*major ABO mismatch allogeneic transplant)
Graft failure/disease relapse/therapy-related myelodysplastic syndromes or acute myeloid leukemia	Bone marrow biopsy, cytogenetics/molecular assessment, peripheral blood or bone marrow chimerism (*allogeneic only)
Graft-versus-host diseas	Clinical suspicion and biopsy of involved organ (*allogeneic only)
Infectious agents	Parvovirus DNA, CMV DNA, EBV PCR, nasal swab, blood and urine culture, chest X-ray or CT (to identify a bacterial or fungal infection)
Endocrine causes	Check TSH and T4 level, ACTH and cortisol level (if clinical suspicion for hypothyroidism and adrenal insufficiency)
Drug-induced bone marrow suppression	If other causes are excluded, suspend suspected medication
Reticulocytosis
Transplant-associated thrombotic microangiopathy	Blood smear, LDH, haptoglobin, DAT, urine protein/creatinine ratio, sC5b-9, ADAMTS13 in selected cases
ABO mismatch	LDH, haptoglobin, DAT, isohemaglutinin titer (*early period of allogeneic transplant)
Autoimmune hemolytic anemia	Blood smear, LDH, haptoglobin, DAT
Drug-induced hemolytic anemia	Blood smear, LDH, haptoglobin, DAT

ACTH, adrenocorticotropic hormone; CMA, cytomegalovirus; CT, computed tomography; DAT, direct antiglobulin test; DNA, deoxyribonucleic acid; EBV, Epstein-Barr virus; LDH, lactate dehydrogenase; PCR, polymerase chain reaction; sC5b-9, soluble C5b-9; TSH, thyroid-stimulating hormone; T4, thyroxine.

The patient’s initial workup consisted of the following items:

Viral serologies: All infectious-related viral immunoglobulin M (IgM) markers (parvovirus, herpes simplex virus 1, cytomegalovirus, Epstein-Barr virus viral capsid antigen, anti-hemoglobin C, hepatitis C virus IgM) and human immunodeficiency virus antigen/antibody combo test were negative.
Nutritional assessment: no deficiencies in vitamin B12, folate, or iron
Normal thyroid-stimulating horome and serum thyroxine level
PET-CT and cranial magnetic resonance imaging: no evidence of relapse

BM biopsy revealed profound erythroid aplasia with giant pronormoblasts, while overall cellularity remained normal. Peripheral blood parvovirus deoxyribonucleic acid (DNA) was detected at greater than 15 million copies, confirming active parvovirus infection despite the absence of serum IgM positivity.

The patient was diagnosed with pure red cell aplasia (PRCA) due to human parvovirus B19 (HPV-B19) infection. Given the high viral load and post-transplant immunosuppression, intravenous immunoglobulin (IVIG) therapy at 400 mg/kg/d for five days was initiated.

The patient’s hemoglobin levels and viral load were monitored to assess response to IVIG, which resulted in successful recovery, with gradual improvement in hemoglobin levels and resolution of anemia (Figures 1 & 2).

Figure 1. Parvovirus DNA trend

Figure 2. Hemoglobin trend

Follow-up testing showed a significant decline in parvovirus DNA load, confirming effective viral clearance. The patient remained stable without recurrence of anemia.

PRCA is a rare disease that presents with anemia secondary to erythropoiesis failure. It is characterized by normocytic, normochromic anemia associated with reticulocytopenia in the peripheral blood and a sparse presence or absence of erythroblasts and giant pronormoblasts in the BM.¹ In hosts with chronic hemolysis or immunosuppression, PRCA may occur due to HPV-B19.² In the literature, HPV-B19-associated PRCA is seen more frequently in the early period after transplant. In immunocompromised hosts, serological tests may yield negative results. Consequently, parvovirus DNA polymerase chain reaction (PCR) analysis should be performed for an accurate diagnosis.³

The recommended treatment for HPV-B19 associated with PRCA includes dose reduction if there is ongoing immunosuppression, change of calcineurin inhibitor, and passive immunization with IVIG. According to current guidelines, standard therapy against HPV-B19 infection consists of IVIG in a total dose of 2 g/kg in five divided doses.⁴ Although antiviral medications are not considered effective treatment options for HPV-B19 infection, recent studies have demonstrated the efficacy of foscarnet in cases of relapsed or unresponsive parvovirus infection following IVIG treatment.⁵

In conclusion, it is recommended that HPV-B19 infection be considered in the differential diagnosis of anemia with reticulocytopenia in immunocompromised patients. It is acknowledged that standard HPV-B19 serological tests may not detect HPV-B19 infection. Consequently, HPV-B19 PCR testing should be performed when there is clinical suspicion.

Sawada K, Fujishima N, Hirokawa M. Acquired pure red cell aplasia: updated review of treatment. Br J Haematol. 2008;142:505-514.
Brown KE, Young NS. Parvovirus B19 infection and hematopoiesis. Blood Rev. 1995;9(3):176-182.
Ersal T, Özkalemkaş F, Özkocaman V, et al. Two cases of kidney transplant recipients with multiple relapsing pure red cell aplasia due to parvovirus B19 infection. Exp Clin Transplant. 2024;22(1):75-79.
Liefeldt L, Buhl M, Schweickert B, et al. Eradication of parvovirus B19 infection after renal transplantation requires reduction of immunosuppression and high-dose immunoglobulin therapy. Nephrol Dial Transplant. 2002;17(10):1840-1842.
Yu Y, Bao R, Lyu J, et al. Foscarnet therapy for pure red cell aplasia related to human parvovirus B19 infection in kidney transplant recipients: a preliminary exploration. Infect Drug Resist. 2021;14:2911-2923.

Disclosure Statement: Drs. Gülderen and Hunutlu indicated no relevant conflicts of interest.

Acknowledgment: This article was reviewed by Jeffrey Edwards, MD, MPH, and Pallawi Torka, MD, MBBS.