CTCL Is Rare, Incurable, and Potentially Lethal in Advanced Stages

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Partner | Cancer Centers | <b>Moffitt Cancer Center</b>

Although cutaneous T-cell lymphoma, a group of non-Hodgkin T-cell lymphomas, remains a rare disease, incidence has increased steadily since the 1970s.

Although cutaneous T-cell lymphoma (CTCL), a group of non-Hodgkin T-cell lymphomas, remains a rare disease, incidence has increased steadily since the 1970s. Over that same period, investigators also observed a trend toward increasing 5-year overall survival (OS) since 1973, plateauing at 78.3% from 1997 to 2005.1

As reported by the Surveillance, Epidemiology and End Results (SEER) registry data, annual overall incidence in the United States was 6.4 cases per million persons from 1973 to 2002, increasing to 7.7 per million persons in 2001 to 2005.2,3

The most common form of CTCL, mycosis fungoides (MF) accounts for upward of 60% of CTCLs. MF is characterized by cutaneous patch, plaque, or tumor lesions. Sézary syndrome, the leukemic variant of CTCL with circulating malignant T-cells in the peripheral blood, accounts for approximately 3% to 5% of CTCLs.4

Large cell transformation (LCT) occurs in a subset of patients with MF and Sezary syndrome, when the lymphoma cells undergo histopathologic transition from neoplastic small-medium sized lymphocytes to large, blast-like T-cells. The incidence of LCT in patients with early-stage disease is 1.4%, compared with 27% in those with stage IIB disease and 56% to 67% in those with stage IV disease.5

The primary site of detectable transformation is the skin. Similar to Richter transformation in chronic lymphocytic leukemia, transformation in CTCL portends an immediate transition to aggressive clinical behavior—especially for those who transform within 2 years of MF diagnosis; it is also linked with a rapid decline in survival and resistance to multiple forms of therapy.6,7

Median age at diagnosis is 55 years to 60 years, and risk increases with age. Men are more likely to develop the disease compared with women (overall annual age-adjusted incidence, 8.7 × 10-6 vs 4.6 × 10-6).8 Large-scale SEER and National Cancer Database studies showed that Black/African American patients have a higher incidence rate, younger age of onset, higher disease burden, and inferior survival compared with their White counterparts. These trends hold even after accounting for disease characteristics, socioeconomic factors and treatments received.9,10

Pei-Ling Chen, MD, PhD, a member of the Pathology and Cutaneous Oncology Departments at Moffitt Cancer Center and a member of the Moffitt Cutaneous Lymphoma Multidisciplinary Clinic, recently published a new study done in patients with CTCL with large cell transformation (transformed CTCL); this occurs when a specific subset of MF tumor cells undergoes molecular and/or genetic changes that cause them to become an aggressive large cell lymphoma.

Early-stage disease presents with scaly patches alone, or patches and plaques of different shapes and sizes, commonly located on the sun-protected areas of the body. At this point, CTCL can look like several skin conditions, making it one of the most challenging diseases to diagnose.

“Sometimes 1 biopsy is not enough,” Chen said. “You need serial biopsies. It can take many years to confirm a diagnosis of cutaneous T-cell lymphoma.”

She added that management often requires a multidisciplinary team of specialists in dermatology, hematology/oncology, dermatopathology, and radiation oncology who have expertise in cutaneous lymphoma, especially for those with advanced disease.

Patients with early-stage disease typically receive skin-directed therapies, such as topical steroids, UVB and PUVA phototherapy, and local radiation. Those with advanced disease or SS often require multiple lines and recurrent courses of systemic therapies.

MF staging is classified into stages IA through IVB using tumor (T, patches or plaques), lymph node (N), metastasis (M), and blood involvement (B) (TNMB).11 Stages IA, IB, and IIA are considered early-stage disease; stages IIB through IVB are considered advanced-stage disease, where the malignant T-cells form tumors or involve the lymph node, blood or other organs.The predicted 10-year overall survival (OS) rate is 90.3% for early-stage disease vs 53.2% for advanced stage disease.12

In findings from a retrospective cross-sectional observational study of 102 patients with stage IA and stage IB MF, investigators observed disease progression (upstaging) in 29.4% of patients.13 In results published in 2015, the reported median OS for patients with stage IIB disease was 68 months compared with 48 months for those with stage IVA disease and 33 months for those with stage IVB disease. Investigators found that stage IV disease, being older than 60 years of age, having large-cell transformation, and increased lactate dehydrogenase were independent prognostic markers for a worse survival.14

Chen noted that advanced-stage disease can be highly disfiguring and lethal and often fails to respond to multiple forms of systemic therapy. Importantly, the disease biology and response to therapies can be heterogeneous within the skin and across different body compartments when the disease is in advanced stages.

Identifying New Therapeutic Targets

Chen recently published results of a multiomics profiling of 70 FFPE skin biopsies and 16 fresh tissue specimens from 56 patients with transformed CTCL that may shed some light on the genomic landscape and novel therapeutic vulnerabilities of this disease. She and her team investigated the tumor ecosystem using integrative approaches spanning whole-exome sequencing, single-cell RNAseq and immune profiling by single-cell V(D)J sequencing and multiplex immunofluorescence studies.15

Whole-exome sequencing identified high tumor mutation burden, UV signatures that are prognostic for survival, exome-based driver events, and most recurrently mutated pathways in transformed CTCL. Single-cell profiling of 16 skin biopsies identified a core oncogenic program with metabolic reprogramming toward oxidative phosphorylation, cellular plasticity, upregulation of MYC and E2F activities, and downregulation of MHC I suggestive of immune escape.

“From the whole-exome sequencing data, we observed UV signatures as the dominant mutation signature in transformed CTCL. When we stratified the mutation signature data by race and compared the mutations signatures in Black/African American patients vs White, we saw that the Black/African American patients showed reduced UV signature and enrichment of a unique mutation signature cluster that included a DNA mismatch repair signature,” Chen said. “I think this is the first genomic study providing a glimpse of potential genomic correlate of racial disparity in CTCL. We hypothesize that mutations signatures other than UV signature likely drive worse outcomes in the Black/African American patients.”

Furthermore, her group identified the core oncogenic programs that malignant T cells exploit at large cell transformation, including metabolic reprogramming toward oxidative phosphorylation, cellular plasticity, upregulation of MYC, E2F and macrophage migration inhibitory factor activities, and downregulation of MHC-I suggestive of immune surveillance escape. Long term, Chen hopes these discoveries can lead the development of novel therapeutic strategies for CTCL.

“My study was admittedly a small patient cohort. To understand this disease better, we definitely need to sequence more, and this will likely require a multi-institutional sequencing effort,” she said. “Although our efforts have so far focused on generating comprehensive ‘omics’ data from well-curated clinical samples, to identify therapeutic vulnerabilities, we also need more cell lines, more animal models, and generating these resources has been the challenge given the rarity of this disease.”

Chen noted that although there is a decline in cancer death rates for many common cancers due to advances in precision oncology and novel immunotherapies, there is a sobering under-representation of this success in rare cancers. “The lack of biospecimen to study rare cancers often leads to paucity of genome-level investigation and poor understanding of disease biology,” Chen said. “There is also far less scientific attention and funding resources than the common cancers.”

Ellen Kim, MD, professor of dermatology and dermatology clinic medical director at Perelman Center for Advanced Medicine at the Hospital of the University of Pennsylvania, and her colleagues, have recently had success with synthetic hypericin (HyBryte). Hypericin is a potent photosensitizer applied to skin lesions that is taken up by the malignant T-cells, and then activated by visible light 16 to 24 hours later.

In data from the phase 3 FLASH trial (NCT02448381) published in June 2022, investigators found that hypericin induced a response rate of 16% vs 4% with placebo (P = .04) following 6 weeks of therapy. The response rate in the hypericin arm increased to 49% through 18 weeks of treatment (P <.0001).16

Investigators observed significant clinical response in both patch and plaque type lesions. Moreover, response was consistent across subgroups including age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies.

“This is a novel skin-directed, non-mutagenic photodynamic therapy with a light source that is not carcinogenic,” Chen said. “Results from Dr Kim’s study in JAMA Dermatology showed that significant clinical response was observed both in patch lesions and plaque lesions. This is quite exciting because it can potentially provide an important new therapy for early-stage disease patients with few adverse effects.”

References

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  2. Kim YH, Hoppe RT. Mycosis fungoides and the Sézary syndrome. Semin Oncol. 1999;26(3):276-289.
  3. Vonderheid EC, Bernengo MG, Burg G, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol. 2002;46(1):95-106. doi:10.1067/mjd.2002.118538
  4. Keto, J., Hahtola, S., Linna, M. et al. Mycosis fungoides and Sézary syndrome: a population-wide study on prevalence and health care use in Finland in 1998–2016. BMC Health Serv Res. 2021;21(1):166. doi:10.1186/s12913-021-06109-9
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  11. Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sezary 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 Sep 15;110(6):1713-22. doi:10.1182/blood-2007-03-055749
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