A deep dive into rare diseases: cutaneous T-cell lymphoma

This article delves into cutaneous T-cell lymphoma (CTCL), covering the diagnosis, standard of care, and future treatment directions.

What is CTCL?

Primary cutaneous lymphomas are a heterogeneous group of non-Hodgkin lymphoma (NHL), characterized by a lack of extracutaneous disease at the time of diagnosis.¹ In contrast to most nodal NHL subtypes, which are B-cell derived, approximately 75-80% of primary cutaneous lymphomas arise from the clonal proliferation of malignant CD4+ T-cells and are termed cutaneous T-cell lymphoma.¹ 

The most common CTCL subtypes include mycosis fungoides (MF) and Sézary syndrome (SS). MF is the most prevalent, making up 60% of CTCL cases and almost half of all primary cutaneous lymphomas.² MF typically presents with patch-plaque-stage skin lesions progressing to tumors and systemic involvement, and SS is a leukemic variant characterized by erythroderma, lymphadenopathy, and circulating malignant Sézary cells.³ Although MF and SS are classed as separate entities, SS often evolves from MF and shares much of the same histologic and staging criteria.⁴

Although MF and SS encompass the majority of CTCL cases, at least 12 distinct CTCL subtypes have been identified, with most being rare subtypes comprising <1% to 2% of cases.⁵ These include both indolent and aggressive entities.

The diagnosis of CTCL

In CTCL, the type and stage of disease significantly impact prognosis, meaning that accurate diagnosis and staging are critical to ensure patients receive the most appropriate treatment.⁶ Diagnosing CTCL can be challenging due to shared characteristics with several common skin conditions. Therefore, repeated skin biopsies are necessary, alongside blood tests, imaging, bone marrow and lymph node biopsies, to allow for clinicopathological correlation.³ To accurately differentiate between different sub-types of CTCL, a biopsy of each type of skin lesion should be performed.⁶ 

As the management of CTCL requires a ‘risk-adapted’ approach, patients are risk stratified using the TNMB (tumor, node, metastasis, blood) staging system, which was most recently updated in 2022 by the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC).⁷ Using this system, a clinical stage of disease is determined, and this informs the therapeutic strategy selected for the patient.

The current standard of care for CTCL

At present, no curative treatment exists for CTCL. Currently available therapeutic approaches aim to control symptoms, prevent progression, and improve the quality of life for patients with the disease.⁶

At the 66th ASH Annual Meeting and Exposition in San Diego, CA, Pierluigi Porcu, MD, Sidney Kimmel Cancer Center, Philadelphia, PA, outlined the current standard of care for patients with early-stage disease limited to the skin (stages IA–IIA), as well as for patients with advanced disease with varying levels of nodal, visceral, or blood involvement (IIB–IV).

“For the patient with early stage, the standard of care initially is so-called skin-directed therapy, which includes phototherapy, electromagnetic radiation, topical steroids, and so on. Many of these patients can go on for a fairly long time just rotating through these different skin-directed therapies. 

For the patients with advanced-stage disease, those will need systemic therapy from the very beginning. However, a significant fraction, perhaps the majority, of the patients with early-stage disease will also eventually need systemic therapy because they will stop responding to phototherapy, electron beam, or topical therapy.”

Although Dr Porcu highlights that the standard of care for patients with early-stage disease has not undergone any notable recent changes, the past five to six years have seen significant advancements in the management of patients with advanced-stage disease who have received at least one prior systemic therapy. These include the FDA approval of brentuximab vedotin (BV) in November 2017 based on the results of the Phase III ALCANZA trial (NCT01578499)⁸ and the approval of mogamulizumab in August 2018 supported by data from the Phase III MAVORIC trial (NCT01728805).⁹ Most recently, in August 2024, the agent E7777 (denileukin diftitox-cxdl) was approved by the FDA for patients with CTCL based on results from a Phase III multicenter, open-label, single-arm registrational trial (NCT01871727).¹⁰ This agent is the first to target the IL-2 receptor to kill malignant T-cells and concurrently deplete host Tregs. 

Prior to these approvals, the systemic agents predominantly used in advanced-stage disease included gemcitabine or doxorubicin single-agent chemotherapy, histone deacetylase (HDAC) inhibitors romidepsin and vorinostat, and the dihydrofolate reductase (DHFR) inhibitor pralatrexate.¹¹ Mogamulizumab and BV are associated with longer-term responses and less systemic toxicity than these agents, leading to improved outcomes for patients.¹² 

Despite these promising advancements, allogeneic stem cell transplantation (alloSCT) remains the only potentially curative treatment for advanced CTCL. However, alloSCT is typically reserved for patients with high-risk or multiple relapsed/refractory (R/R) advanced-stage disease due to the high morbidity and mortality associated with the procedure.¹³

Novel therapeutic approaches being explored for CTCL

Several emerging strategies are being explored in CTCL, with a particular focus on immunotherapeutic approaches. Novel agents under investigation include lacutamab, which is being tested in the Phase II TELLOMAK trial (NCT03902184). This first-in-class anti-KIR3DL2 monoclonal antibody was granted Breakthrough Therapy Designation (BTD) by the FDA in February 2025 for the treatment of patients with R/R SS after at least two prior systemic therapies, including mogamulizumab.¹⁴

Immune checkpoint inhibitors such as pembrolizumab, nivolumab, and durvalumab have been trialed for enhancing anti-tumor immunity in the disease, with mixed results.¹¹ Combining these PD-1 inhibitors with lacutamab may be of interest, as decreasing KIR3DL2 expression in vitro was associated with an increased likelihood of response to pembrolizumab.¹⁵

Additionally, various combination regimens are being investigated in CTCL for synergistic efficacy (outlined in Table 1).¹² 

Table 1: Combination therapies under investigation in clinical trials for the treatment of CTCL.

At ASH 2024, Christiane Querfeld, MD, PhD, City of Hope, Duarte, CA, presented the results of a randomized Phase II trial (NCT03011814) assessing the safety and efficacy of durvalumab plus lenalidomide versus single-agent durvalumab in patients with refractory/advanced CTCL. 

“The combination is superior to the single agent, and it has caused response rates that are higher than we’ve ever actually seen within the standard of care in CTCL. … The progression-free survival was 8.5 months in the single arm, and in the combination arm it was not reached, so [the combination therapy is] very exciting.”, Dr Querfeld stated. 

Finally, although CAR T-cell therapy has proved revolutionary in the treatment of B-cell malignancies, its development for CTCL presents several challenges. These include fratricide, inadvertent contamination of the CAR-T product due to the transduction of harvested malignant Sézary T-cells, and on-target/off-tumor toxicity, such as T-cell aplasia.¹⁶ Ongoing early-phase trials are exploring CAR-T products targeting antigens such as CD4, CD7, CD37, CD70, and CCR4 in a range of T-cell malignancies, including CTCL.¹² However, due to the tumor heterogeneity observed in CTCL, it is likely that more complex CAR constructs will need to be developed to optimally treat the disease, leveraging strategies such as multi-targeting and logic gates.¹⁶

These novel agents and treatment strategies offer the potential for improved disease control and better long-term outcomes in CTCL, giving hope to patients with advanced-stage or R/R disease.

To learn more about CTCL from leading experts, be sure to explore our dedicated CTCL channel here.

References

1. Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood. 2019 Jan; 133:1703–1714.
2. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005 May; 105(10):3768-3785.
3. Duhovic C, Child F, Wain EM. Management of cutaneous T-cell lymphoma. Clin Med (Lond). 2012 Apr; 12(2):160-4.
4. Olsen EA, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007 Sept; 110(6):1713-1722.
5. Geller S, Myskowski PL, Pulitzer M, et al. Cutaneous T-cell lymphoma (CTCL), rare subtypes: five case presentations and review of the literature. Chin Clin Oncol. 2019 Feb;8(1):5.
6. Olsen EA. Evaluation, Diagnosis, and Staging of Cutaneous Lymphoma. Dermatol Clin. 2015 Oct; 33(4):643-54.
7. Olsen EA, Whittaker S, Willemze R, et al. Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC. Blood. 2022 Aug 4;140(5):419-437.
8. U.S. Food and Drug Administration. FDA approves Brentuximab vedotin for the treatment of adult patients with primary cutaneous anaplastic large cell lymphoma. Available here. (Last accessed 11/03/2025)
9. U.S. Food and Drug Administration. FDA approves mogamulizumab-kpkc for mycosis fungoides or Sézary syndrome. Available here. (Last accessed 11/03/2025)
10. PR Newswire. Citius Pharmaceuticals receives FDA Approval for LYMPHIR™ (denileukin diftitox-cxdl) immunotherapy for the treatment of adults with relapsed or refractory cutaneous T-cell lymphoma. Available here. (Last accessed 11/03/2025)
11. Stuver R, Geller S. Advances in the treatment of mycoses fungoides and Sézary syndrome: a narrative update in skin-directed therapies and immune-based treatments. Front Immunol. 2023 Oct; 14:1284045.
12. Pelcovits A, Ollila TA, Olszewski AJ. Advances in Immunotherapy for the Treatment of Cutaneous T-Cell Lymphoma. Cancer Manag Res. 2023 Sep; 15:989-998. 
13. Khodadoust MS, Mou E, Kim YH. Integrating novel agents into the treatment of advanced mycosis fungoides and Sézary syndrome. Blood. 2023 Feb; 141(7):695-703.
14. Innate Pharma. Innate Pharma announces U.S. FDA granted breakthrough therapy designation to lacutamab for relapsed or refractory Sézary syndrome. Available here. (Last accessed 11/03/2025)
15. Su T, Duran GE, Kwang AC, et al. Single-cell RNA-sequencing reveals predictive features of response to pembrolizumab in Sézary syndrome. Oncoimmunology. 2022 Aug; 11(1):2115197. 
16. To V, Evtimov VJ, Jenkin G, et al. CAR-T cell development for Cutaneous T cell Lymphoma: current limitations and potential treatment strategies. Front Immunol. 2022 Aug; 13:968395.

Written by Natalie Markova

Edited by Sol Yohannes