JAK Inhibitors in Cutaneous T-Cell Lymphoma: Friend or Foe? A Systematic Review of the Published Literature

Abstract

Cutaneous T-cell lymphomas (CTCLs) are a group of lymphoid neoplasms with high relapse rates and no curative treatment other than allogeneic stem cell transplantation (allo-SCT). CTCL is significantly influenced by disruption of JAK/STAT signaling. Therefore, Janus kinase (JAK) inhibitors may be promising for CTCL treatment. This study is a systematic review aiming to investigate the role of JAK inhibitors in the treatment of CTCL, including their efficacy and safety. Out of 438 initially searched articles, we present 13 eligible ones. The overall response rate (ORR) in the treatment with JAK inhibitors in clinical trials was 11–35%, although different subtypes of CTCL showed different ORRs. Mycosis fungoides showed an ORR of 14–45%, while subcutaneous-panniculitis-like T-cell lymphoma (SPTCL) displayed an ORR ranging from 75% to 100%. Five cases were reported having a relapse/incident of CTCL after using JAK inhibitors; of these, three cases were de novo CTCLs in patients under treatment with a JAK inhibitor due to refractory arthritis, and two cases were relapsed disease after graft-versus-host disease treatment following allo-SCT. In conclusion, using JAK inhibitors for CTCL treatment seems promising with acceptable side effects, especially in patients with SPTCL. Some biomarkers, like pS6, showed an association with better responses. Caution should be taken when treating patients with an underlying autoimmune disease and prior immunosuppression.

Therapeutic Opportunities in Cutaneous T-cell Lymphoma

“…Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas that mainly affect older adults with an incidence of 7.5 per one million people annually. This kind of malignancy starts with mutated T cells that infiltrate into the skin and alter cell interactions in the microenvironment and surrounding skin cells too [1,2].…”

“…The different subtypes of CTCL are characterised by high variability in both clinical and genetic features. The most frequent one is Mycosis fungoides (MF), which represents 55% of CTCL cases, while Sézary syndrome (SS), its leukemic variant, is only 5% of CTCL cases, but is considered the most aggressive CTCL subtype [1][2][3]. MF clinical development goes through patches, plaques, and tumours, compromising the immunological system and even other organs in the tumour stage.…”

“…MF clinical development goes through patches, plaques, and tumours, compromising the immunological system and even other organs in the tumour stage. Meanwhile, SS is a very aggressive subtype with a high recurrence rate and poor prognosis, going through erythroderma, and lymphadenopathy, and it is associated with neoplastic clonal T-cells in the skin, lymph nodes, and peripheral blood [2][3][4].…”

“…There is a wide variety of available therapies such as topical corticosteroids, ultraviolet phototherapy, radiotherapy, total skin electron beam therapy, chemotherapy, and antibodies such as mechlorethamine or bexarotene [2,5]. However, the only curative treatment available is allogeneic stem cell transplantation (alloSCT) [6].…”

“…As mentioned before, MF and SS start with the monoclonal proliferation of effector/central memory CD4+ T-cells growing under an inflammatory landscape. Crucial for the CTCL progression are the interactions that T cells establish with the skin microenvironment, leading to advanced stages and an immune-suppression state with increased risk for infections and decreased antitumour immune response [2,3]. These cell-to-cell interactions are carried out by different signalling networks like JAK/STAT, MAPK/ERK, PI3K/Akt, and NF-kB, among other signalling pathways.…”